SHH_HUMAN
ID SHH_HUMAN Reviewed; 462 AA.
AC Q15465; A4D247; Q75MC9;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 236.
DE RecName: Full=Sonic hedgehog protein {ECO:0000305};
DE Short=SHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=HHG-1;
DE AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000303|PubMed:24522195};
DE Short=ShhNC {ECO:0000303|PubMed:24522195};
DE Contains:
DE RecName: Full=Sonic hedgehog protein N-product;
DE Short=ShhN;
DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000303|PubMed:24522195};
DE Short=ShhNp {ECO:0000303|PubMed:24522195};
DE Flags: Precursor;
GN Name=SHH {ECO:0000312|HGNC:HGNC:10848};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal lung;
RX PubMed=7590746; DOI=10.1006/geno.1995.1104;
RA Marigo V., Roberts D.J., Lee S.M.K., Tsukurov O., Levi T., Gastier J.M.,
RA Epstein D.J., Gilbert D.J., Copeland N.G., Seidman C.E., Jenkins N.A.,
RA Seidman J.G., McMahon A.P., Tabin C.;
RT "Cloning, expression, and chromosomal location of SHH and IHH: two human
RT homologues of the Drosophila segment polarity gene hedgehog.";
RL Genomics 28:44-51(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Tate G., Kishimoto K., Mitsuya T.;
RT "Expression of Sonic hedgehog and its receptor Patched/Smoothened in human
RT cancer cell lines and embryonic organs.";
RL J. Biochem. Mol. Biol. Biophys. 4:27-34(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [6]
RP PROTEIN SEQUENCE OF 24-32, PALMITOYLATION AT CYS-24, CHOLESTERYLATION,
RP MUTAGENESIS OF CYS-24, AND MASS SPECTROMETRY.
RX PubMed=9593755; DOI=10.1074/jbc.273.22.14037;
RA Pepinsky R.B., Zeng C., Wen D., Rayhorn P., Baker D.P., Williams K.P.,
RA Bixler S.A., Ambrose C.M., Garber E.A., Miatkowski K., Taylor F.R.,
RA Wang E.A., Galdes A.;
RT "Identification of a palmitic acid-modified form of human Sonic hedgehog.";
RL J. Biol. Chem. 273:14037-14045(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 119-167.
RX PubMed=7720571; DOI=10.1242/dev.120.11.3339;
RA Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R.,
RA Seldin M.F., Fallon J.F., Beachy P.A.;
RT "Products, genetic linkage and limb patterning activity of a murine
RT hedgehog gene.";
RL Development 120:3339-3353(1994).
RN [8]
RP INVOLVEMENT IN TPTPS, AND INVOLVEMENT IN PPD2.
RX PubMed=12837695; DOI=10.1093/hmg/ddg180;
RA Lettice L.A., Heaney S.J.H., Purdie L.A., Li L., de Beer P., Oostra B.A.,
RA Goode D., Elgar G., Hill R.E., de Graaff E.;
RT "A long-range Shh enhancer regulates expression in the developing limb and
RT fin and is associated with preaxial polydactyly.";
RL Hum. Mol. Genet. 12:1725-1735(2003).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [10]
RP PALMITOYLATION AT CYS-24, MUTAGENESIS OF CYS-24, AND SUBCELLULAR LOCATION.
RX PubMed=18534984; DOI=10.1074/jbc.m803901200;
RA Buglino J.A., Resh M.D.;
RT "Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation
RT of Sonic Hedgehog.";
RL J. Biol. Chem. 283:22076-22088(2008).
RN [11]
RP INVOLVEMENT IN TPTPS.
RX PubMed=18417549; DOI=10.1136/jmg.2008.057646;
RA Sun M., Ma F., Zeng X., Liu Q., Zhao X.-L., Wu F.-X., Wu G.-P.,
RA Zhang Z.-F., Gu B., Zhao Y.-F., Tian S.-H., Lin B., Kong X.-Y.,
RA Zhang X.-L., Yang W., Lo W.H.-Y., Zhang X.;
RT "Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
RT caused by genomic duplications involving the long range, limb-specific SHH
RT enhancer.";
RL J. Med. Genet. 45:589-595(2008).
RN [12]
RP INVOLVEMENT IN THYP.
RX PubMed=19847792; DOI=10.1002/humu.21142;
RA Wieczorek D., Pawlik B., Li Y., Akarsu N.A., Caliebe A., May K.J.,
RA Schweiger B., Vargas F.R., Balci S., Gillessen-Kaesbach G., Wollnik B.;
RT "A specific mutation in the distant sonic hedgehog (SHH) cis-regulator
RT (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS
RT duplications underlie Haas type polysyndactyly and preaxial polydactyly
RT (PPD) with or without triphalangeal thumb.";
RL Hum. Mutat. 31:81-89(2010).
RN [13]
RP INTERACTION WITH DISP1 AND SCUBE2, SUBUNIT, AND CAUTION.
RX PubMed=22902404; DOI=10.1016/j.celrep.2012.07.010;
RA Tukachinsky H., Kuzmickas R.P., Jao C.Y., Liu J., Salic A.;
RT "Dispatched and scube mediate the efficient secretion of the cholesterol-
RT modified hedgehog ligand.";
RL Cell Rep. 2:308-320(2012).
RN [14]
RP PALMITOYLATION AT CYS-24, AND MUTAGENESIS OF CYS-24.
RX PubMed=31875564; DOI=10.1016/j.celrep.2019.11.110;
RA Asciolla J.J., Resh M.D.;
RT "Hedgehog Acyltransferase Promotes Uptake of Palmitoyl-CoA across the
RT Endoplasmic Reticulum Membrane.";
RL Cell Rep. 29:4608-4619(2019).
RN [15]
RP INTERACTION WITH SCUBE2, SUBUNIT, AND CAUTION.
RX PubMed=22677548; DOI=10.1101/gad.191866.112;
RA Creanga A., Glenn T.D., Mann R.K., Saunders A.M., Talbot W.S., Beachy P.A.;
RT "Scube/You activity mediates release of dually lipid-modified Hedgehog
RT signal in soluble form.";
RL Genes Dev. 26:1312-1325(2012).
RN [16]
RP PTM, AND DOMAIN.
RX PubMed=23118222; DOI=10.1074/jbc.m112.356667;
RA Ohlig S., Pickhinke U., Sirko S., Bandari S., Hoffmann D., Dreier R.,
RA Farshi P., Goetz M., Grobe K.;
RT "An emerging role of Sonic hedgehog shedding as a modulator of heparan
RT sulfate interactions.";
RL J. Biol. Chem. 287:43708-43719(2012).
RN [17]
RP REVIEW.
RX PubMed=23154980; DOI=10.1101/gad.207126.112;
RA Ingham P.W.;
RT "Zebrafish genetics gets the Scube on Hedgehog secretion.";
RL Genes Dev. 26:2468-2470(2012).
RN [18]
RP PTM, INTERACTION WITH SCUBE2, SUBUNIT, SUBCELLULAR LOCATION, FUNCTION, AND
RP CAUTION.
RX PubMed=24522195; DOI=10.1242/jcs.137695;
RA Jakobs P., Exner S., Schuermann S., Pickhinke U., Bandari S., Ortmann C.,
RA Kupich S., Schulz P., Hansen U., Seidler D.G., Grobe K.;
RT "Scube2 enhances proteolytic Shh processing from the surface of Shh-
RT producing cells.";
RL J. Cell Sci. 127:1726-1737(2014).
RN [19]
RP SUBCELLULAR LOCATION.
RX PubMed=24342078; DOI=10.1016/j.mod.2013.12.002;
RA Pettigrew C.A., Asp E., Emerson C.P. Jr.;
RT "A new role for Hedgehogs in juxtacrine signaling.";
RL Mech. Dev. 131:137-149(2014).
RN [20]
RP INVOLVEMENT IN LSS.
RX PubMed=24456159; DOI=10.1111/cge.12352;
RA Lohan S., Spielmann M., Doelken S.C., Floettmann R., Muhammad F.,
RA Baig S.M., Wajid M., Huelsemann W., Habenicht R., Kjaer K.W., Patil S.J.,
RA Girisha K.M., Abarca-Barriga H.H., Mundlos S., Klopocki E.;
RT "Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
RT associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.";
RL Clin. Genet. 86:318-325(2014).
RN [21]
RP INVOLVEMENT IN THYP.
RX PubMed=24965254; DOI=10.1038/jhg.2014.50;
RA Norbnop P., Srichomthong C., Suphapeetiporn K., Shotelersuk V.;
RT "ZRS 406A>G mutation in patients with tibial hypoplasia, polydactyly and
RT triphalangeal first fingers.";
RL J. Hum. Genet. 59:467-470(2014).
RN [22]
RP REVIEW, AND FUNCTION.
RX PubMed=24863049; DOI=10.1002/dneu.22193;
RA Pal K., Mukhopadhyay S.;
RT "Primary cilium and sonic hedgehog signaling during neural tube patterning:
RT role of GPCRs and second messengers.";
RL Dev. Neurobiol. 75:337-348(2015).
RN [23]
RP REVIEW, CAUTION, SUBCELLULAR LOCATION, AND PTM.
RX PubMed=26875496; DOI=10.1016/j.ydbio.2016.02.009;
RA Xavier G.M., Seppala M., Barrell W., Birjandi A.A., Geoghegan F.,
RA Cobourne M.T.;
RT "Hedgehog receptor function during craniofacial development.";
RL Dev. Biol. 415:198-215(2016).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 25-197 IN COMPLEX WITH ZINC IONS,
RP FUNCTION, DOMAIN, AND SUBUNIT.
RX PubMed=10753901; DOI=10.1074/jbc.275.15.10995;
RA Pepinsky R.B., Rayhorn P., Day E.S., Dergay A., Williams K.P., Galdes A.,
RA Taylor F.R., Boriack-Sjodin P.A., Garber E.A.;
RT "Mapping sonic hedgehog-receptor interactions by steric interference.";
RL J. Biol. Chem. 275:10995-11001(2000).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 29-197 IN COMPLEX WITH HHIP; ZINC
RP AND CALCIUM IONS, DOMAIN, INTERACTION WITH HHIP, AND SUBUNIT.
RX PubMed=19561609; DOI=10.1038/nsmb.1632;
RA Bosanac I., Maun H.R., Scales S.J., Wen X., Lingel A., Bazan J.F.,
RA de Sauvage F.J., Hymowitz S.G., Lazarus R.A.;
RT "The structure of SHH in complex with HHIP reveals a recognition role for
RT the Shh pseudo active site in signaling.";
RL Nat. Struct. Mol. Biol. 16:691-697(2009).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 29-197 IN COMPLEX WITH MONOCLONAL
RP ANTIBODY; ZINC AND CALCIUM IONS, AND DOMAIN.
RX PubMed=20504762; DOI=10.1074/jbc.m110.112284;
RA Maun H.R., Wen X., Lingel A., de Sauvage F.J., Lazarus R.A., Scales S.J.,
RA Hymowitz S.G.;
RT "Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active
RT site.";
RL J. Biol. Chem. 285:26570-26580(2010).
RN [27]
RP VARIANTS HPE3 ARG-31; GLY-117 AND ARG-117.
RX PubMed=8896572; DOI=10.1038/ng1196-357;
RA Roessler E., Belloni E., Gaudenz K., Jay P., Berta P., Scherer S.W.,
RA Tsui L.-C., Muenke M.;
RT "Mutations in the human Sonic hedgehog gene cause holoprosencephaly.";
RL Nat. Genet. 14:357-360(1996).
RN [28]
RP VARIANTS HPE3 ARG-31; GLY-117; ARG-117; GLU-224; THR-226 AND THR-383.
RX PubMed=9302262; DOI=10.1093/hmg/6.11.1847;
RA Roessler E., Belloni E., Gaudenz K., Vargas F., Scherer S.W., Tsui L.-C.,
RA Muenke M.;
RT "Mutations in the C-terminal domain of Sonic hedgehog cause
RT holoprosencephaly.";
RL Hum. Mol. Genet. 6:1847-1853(1997).
RN [29]
RP VARIANTS HPE3 HIS-100; GLN-188 AND ASN-222.
RX PubMed=10441331; DOI=10.1093/hmg/8.9.1683;
RA Odent S., Atti-Bitach T., Blayau M., Mathieu M., Aug J., Delezo de A.L.,
RA Gall J.Y., Le Marec B., Munnich A., David V., Vekemans M.;
RT "Expression of the Sonic hedgehog (SHH) gene during early human development
RT and phenotypic expression of new mutations causing holoprosencephaly.";
RL Hum. Mol. Genet. 8:1683-1689(1999).
RN [30]
RP VARIANTS HPE3 VAL-88; LYS-115; ARG-236; 263-ARG--ALA-269 DEL; ASP-290;
RP ALA-424 AND LEU-436.
RX PubMed=10556296; DOI=10.1093/hmg/8.13.2479;
RA Nanni L., Ming J.E., Bocian M., Steinhaus K., Bianchi D.W.,
RA Die-Smulders C., Giannotti A., Imaizumi K., Jones K.L., Campo M.D.,
RA Martin R.A., Meinecke P., Pierpont M.E.M., Robin N.H., Young I.D.,
RA Roessler E., Muenke M.;
RT "The mutational spectrum of the sonic hedgehog gene in holoprosencephaly:
RT SHH mutations cause a significant proportion of autosomal dominant
RT holoprosencephaly.";
RL Hum. Mol. Genet. 8:2479-2488(1999).
RN [31]
RP VARIANT SMMCI PHE-111.
RX PubMed=11471164;
RX DOI=10.1002/1096-8628(20010722)102:1<1::aid-ajmg1336>3.0.co;2-u;
RA Nanni L., Ming J.E., Du Y., Hall R.K., Aldred M., Bankier A., Muenke M.;
RT "SHH mutation is associated with solitary median maxillary central incisor:
RT a study of 13 patients and review of the literature.";
RL Am. J. Med. Genet. 102:1-10(2001).
RN [32]
RP VARIANTS HPE3 PRO-140 AND PHE-183.
RX PubMed=11479728; DOI=10.1007/s004390100537;
RA Orioli I.M., Castilla E.E., Ming J.E., Nazer J., Burle de Aguiar M.J.,
RA Llerena J.C., Muenke M.;
RT "Identification of novel mutations in SHH and ZIC2 in a South American
RT (ECLAMC) population with holoprosencephaly.";
RL Hum. Genet. 109:1-6(2001).
RN [33]
RP VARIANT MCOPCB5 401-SER--GLY-408 DEL.
RX PubMed=12503095; DOI=10.1002/ajmg.a.10884;
RA Schimmenti L.A., de la Cruz J., Lewis R.A., Karkera J.D., Manligas G.S.,
RA Roessler E., Muenke M.;
RT "Novel mutation in sonic hedgehog in non-syndromic colobomatous
RT microphthalmia.";
RL Am. J. Med. Genet. A 116:215-221(2003).
RN [34]
RP VARIANT SMMCI ALA-332.
RX PubMed=15103725; DOI=10.1002/ajmg.a.20685;
RA Garavelli L., Zanacca C., Caselli G., Banchini G., Dubourg C., David V.,
RA Odent S., Gurrieri F., Neri G.;
RT "Solitary median maxillary central incisor syndrome: clinical case with a
RT novel mutation of sonic hedgehog.";
RL Am. J. Med. Genet. A 127:93-95(2004).
RN [35]
RP VARIANTS HPE3 ALA-27; ILE-267 AND THR-373.
RX PubMed=15107988; DOI=10.1007/s00431-004-1459-0;
RA Hehr U., Gross C., Diebold U., Wahl D., Beudt U., Heidemann P., Hehr A.,
RA Mueller D.;
RT "Wide phenotypic variability in families with holoprosencephaly and a sonic
RT hedgehog mutation.";
RL Eur. J. Pediatr. 163:347-352(2004).
RN [36]
RP VARIANTS HPE3 THR-6; HIS-100; 106-LEU-ASN-107 DEL; ASP-110; ARG-150;
RP 176-GLU--LYS-178 DEL; GLN-188; ASN-222; PRO-271; ALA-332; GLN-347; THR-354
RP AND PRO-381.
RX PubMed=15221788; DOI=10.1002/humu.20056;
RA Dubourg C., Lazaro L., Pasquier L., Bendavid C., Blayau M., Le Duff F.,
RA Durou M.-R., Odent S., David V.;
RT "Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with
RT features of holoprosencephaly spectrum: mutation review and genotype-
RT phenotype correlations.";
RL Hum. Mutat. 24:43-51(2004).
RN [37]
RP VARIANT HPE3 ASN-111.
RX PubMed=15942952; DOI=10.1002/ajmg.a.30624;
RA El-Jaick K.B., Brunoni D., Castilla E.E., Moreira M.A., Orioli I.M.;
RT "SHH Ile111Asp in alobar holoprosencephaly in a proposita, whose mother had
RT only a solitary median maxillary incisor.";
RL Am. J. Med. Genet. A 136:345-345(2005).
RN [38]
RP VARIANT HPE3 GLN-140.
RX PubMed=15942953; DOI=10.1002/ajmg.a.30625;
RA Ribeiro L.A., Richieri-Costa A.;
RT "Single median maxillary central incisor, hypophyseal tumor, and SHH
RT mutation.";
RL Am. J. Med. Genet. A 136:346-347(2005).
RN [39]
RP CHARACTERIZATION OF VARIANTS HPE3 ARG-31; VAL-88; HIS-100; LYS-115;
RP ARG-117; GLY-117 AND GLN-188.
RX PubMed=16282375; DOI=10.1073/pnas.0507848102;
RA Maity T., Fuse N., Beachy P.A.;
RT "Molecular mechanisms of Sonic hedgehog mutant effects in
RT holoprosencephaly.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:17026-17031(2005).
RN [40]
RP VARIANTS HPE3 GLN-140; PRO-218 AND TYR-363.
RX PubMed=17001669; DOI=10.1002/ajmg.a.31378;
RA Richieri-Costa A., Ribeiro L.A.;
RT "Holoprosencephaly-like phenotype: clinical and genetic perspectives.";
RL Am. J. Med. Genet. A 140:2587-2593(2006).
RN [41]
RP VARIANTS HPE3 THR-6; PRO-17; LEU-26; ALA-27; ARG-31; PRO-39; LYS-53;
RP VAL-83; PHE-84; VAL-88; HIS-100; ARG-102; TYR-102; 106-LEU-ASN-107 DEL;
RP PHE-109; THR-110; ASP-110; PHE-111; ASN-111; LYS-115; GLY-117; ARG-117;
RP MET-124; LYS-136; PRO-140; GLN-140; ASP-143; PRO-144; ASN-147; ARG-150;
RP LYS-150; ARG-156; CYS-170; HIS-171; 176-GLU--LYS-178 DEL; ARG-183; PHE-183;
RP TYR-183; LEU-184; GLN-188; GLU-196; 196-GLY--PRO-200 DEL; VAL-197; SER-198;
RP PHE-198; PRO-218; ASN-222; GLU-224; THR-226; VAL-231; GLY-232; PRO-234;
RP ARG-236; ASN-236; VAL-241; LEU-241; ASN-255; 263-ARG--ALA-269 DEL; ILE-267;
RP PRO-271; GLU-275; TRP-280; ASP-290; ALA-296; CYS-310; SER-321; ALA-332;
RP VAL-346; ARG-347; GLN-347; LEU-347; THR-354; LEU-362; TYR-363; CYS-364;
RP THR-373; ARG-374; ASP-376; SER-377; 378-ALA--PHE-380 DEL; PRO-381; PRO-382;
RP THR-383; THR-391; 402-GLY--GLY-409 DEL; 405-ASP--GLY-409 DEL; GLY-411 INS;
RP ALA-416; ALA-424; ASN-435; LEU-436 AND ARG-456.
RX PubMed=19603532; DOI=10.1002/humu.21090;
RA Roessler E., El-Jaick K.B., Dubourg C., Velez J.I., Solomon B.D.,
RA Pineda-Alvarez D.E., Lacbawan F., Zhou N., Ouspenskaia M., Paulussen A.,
RA Smeets H.J., Hehr U., Bendavid C., Bale S., Odent S., David V., Muenke M.;
RT "The mutational spectrum of holoprosencephaly-associated changes within the
RT SHH gene in humans predicts loss-of-function through either key structural
RT alterations of the ligand or its altered synthesis.";
RL Hum. Mutat. 30:E921-E935(2009).
CC -!- FUNCTION: [Sonic hedgehog protein]: The C-terminal part of the sonic
CC hedgehog protein precursor displays an autoproteolysis and a
CC cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein into two parts (ShhN
CC and ShhC) followed by the covalent attachment of a cholesterol moiety
CC to the C-terminal of the newly generated ShhN (By similarity). Both
CC activities occur in the reticulum endoplasmic (By similarity). Once
CC cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated
CC sonic hedgehog protein N-product (ShhNp) is a morphogen which is
CC essential for a variety of patterning events during development.
CC Induces ventral cell fate in the neural tube and somites
CC (PubMed:24863049). Involved in the patterning of the anterior-posterior
CC axis of the developing limb bud (By similarity). Essential for axon
CC guidance (By similarity). Binds to the patched (PTCH1) receptor, which
CC functions in association with smoothened (SMO), to activate the
CC transcription of target genes (PubMed:10753901). In the absence of SHH,
CC PTCH1 represses the constitutive signaling activity of SMO
CC (PubMed:10753901). {ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:24863049,
CC ECO:0000303|PubMed:24522195}.
CC -!- CATALYTIC ACTIVITY: [Sonic hedgehog protein]:
CC Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]-
CC C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-
CC [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA-
CC COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135,
CC ChEBI:CHEBI:143140; Evidence={ECO:0000250|UniProtKB:Q62226};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505;
CC Evidence={ECO:0000250|UniProtKB:Q62226};
CC -!- SUBUNIT: [Sonic hedgehog protein N-product]: Multimer.
CC {ECO:0000269|PubMed:24522195}.
CC -!- SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-
CC mediated palmitoylation of the SHH N-terminus (By similarity).
CC Interacts with BOC and CDON (By similarity). Interacts with HHIP
CC (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor
CC (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2
CC (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3 (By
CC similarity). {ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:19561609, ECO:0000269|PubMed:22677548,
CC ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:24522195}.
CC -!- INTERACTION:
CC Q15465; Q96QV1: HHIP; NbExp=10; IntAct=EBI-11666886, EBI-6598521;
CC Q15465; Q13635: PTCH1; NbExp=2; IntAct=EBI-11666886, EBI-8775406;
CC Q15465; Q13635-1: PTCH1; NbExp=4; IntAct=EBI-11666886, EBI-13635488;
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000305|PubMed:18534984}. Golgi apparatus membrane
CC {ECO:0000305|PubMed:18534984}. Secreted {ECO:0000269|PubMed:24342078}.
CC Note=Co-localizes with HHAT in the ER and Golgi membrane.
CC {ECO:0000305|PubMed:18534984}.
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Cell membrane
CC {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q62226}. Note=The dual-lipidated sonic hedgehog
CC protein N-product (ShhNp) is firmly tethered to the cell membrane where
CC it forms multimers (PubMed:24522195). Further solubilization and
CC release from the cell surface seem to be achieved through different
CC mechanisms, including the interaction with DISP1 and SCUBE2, movement
CC by lipoprotein particles, transport by cellular extensions called
CC cytonemes or by the proteolytic removal of both terminal lipidated
CC peptides (PubMed:26875496, PubMed:24522195).
CC {ECO:0000305|PubMed:24522195, ECO:0000305|PubMed:26875496}.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: Binds calcium and zinc
CC ions; this stabilizes the protein fold and is essential for protein-
CC protein interactions mediated by this domain.
CC {ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:19561609,
CC ECO:0000269|PubMed:20504762}.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW)
CC motif is required for heparan sulfate binding of the solubilized ShhNp
CC (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at
CC the heparan sulfate-binding Cardin-Weintraub (CW) motif site
CC (PubMed:24522195). The cleavage reduced the interactions with heparan
CC sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).
CC {ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein]: The C-terminal domain displays an
CC autoproteolysis activity and a cholesterol transferase activity (By
CC similarity). Both activities result in the cleavage of the full-length
CC protein and covalent attachment of a cholesterol moiety to the C-
CC terminal of the newly generated N-terminal fragment (ShhN) (By
CC similarity). Cholesterylation is required for the sonic hedgehog
CC protein N-product targeting to lipid rafts and multimerization
CC (PubMed:24522195, PubMed:26875496). ShhN is the active species in both
CC local and long-range signaling, whereas the C-product (ShhC) is
CC degraded in the reticulum endoplasmic (By similarity).
CC {ECO:0000250|UniProtKB:Q62226, ECO:0000303|PubMed:26875496,
CC ECO:0000305|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein N-product]: N-palmitoylation by HHAT of
CC ShhN is required for sonic hedgehog protein N-product multimerization
CC and full activity (By similarity). It is a prerequisite for the
CC membrane-proximal positioning and the subsequent shedding of this N-
CC terminal peptide (PubMed:24522195). {ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C-
CC terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195).
CC The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub
CC (CW) motif site (PubMed:24522195). The cleavage reduced the
CC interactions with heparan sulfate. The cleavage is enhanced by SCUBE2
CC (PubMed:24522195, PubMed:23118222). {ECO:0000269|PubMed:23118222,
CC ECO:0000269|PubMed:24522195}.
CC -!- MASS SPECTROMETRY: [Sonic hedgehog protein N-product]: Mass=19.560;
CC Method=Electrospray; Note=Sonic hedgehog protein N-product: soluble
CC product, purified from insect cells.;
CC Evidence={ECO:0000269|PubMed:9593755};
CC -!- MASS SPECTROMETRY: [Sonic hedgehog protein N-product]: Mass=20.167;
CC Method=Electrospray; Note=Sonic hedgehog protein N-product: Membrane-
CC bound product, purified from insect cells.;
CC Evidence={ECO:0000269|PubMed:9593755};
CC -!- DISEASE: Microphthalmia, isolated, with coloboma, 5 (MCOPCB5)
CC [MIM:611638]: A disorder of eye formation, ranging from small size of a
CC single eye to complete bilateral absence of ocular tissues. Ocular
CC abnormalities like opacities of the cornea and lens, scaring of the
CC retina and choroid, and other abnormalities may also be present. Ocular
CC colobomas are a set of malformations resulting from abnormal
CC morphogenesis of the optic cup and stalk, and the fusion of the fetal
CC fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly
CC of the brain, in which the developing forebrain fails to correctly
CC separate into right and left hemispheres. Holoprosencephaly is
CC genetically heterogeneous and associated with several distinct facies
CC and phenotypic variability. The majority of holoprosencephaly type 3
CC cases are apparently sporadic, although clear examples of autosomal
CC dominant inheritance have been described. {ECO:0000269|PubMed:10441331,
CC ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728,
CC ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788,
CC ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953,
CC ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669,
CC ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
CC ECO:0000269|PubMed:9302262}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Solitary median maxillary central incisor (SMMCI)
CC [MIM:147250]: Rare dental anomaly characterized by the congenital
CC absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164,
CC ECO:0000269|PubMed:15103725}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Triphalangeal thumb-polysyndactyly syndrome (TPTPS)
CC [MIM:174500]: Autosomal dominant syndrome. It is characterized by a
CC wide spectrum of pre- and post-axial abnormalities due to altered SHH
CC expression pattern during limb development.
CC {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The
CC gene represented in this entry is involved in disease pathogenesis.
CC Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-
CC regulatory element of SHH expression.
CC -!- DISEASE: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly
CC consists of duplication of the distal phalanx. The thumb in PPD2 is
CC usually opposable and possesses a normal metacarpal.
CC {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry
CC is involved in disease pathogenesis. Mutations located in intron 5 of
CC LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in
CC abnormal, ectopic SHH expression with pathological consequences
CC (PubMed:12837695). {ECO:0000269|PubMed:12837695}.
CC -!- DISEASE: Hypoplasia or aplasia of tibia with polydactyly (THYP)
CC [MIM:188740]: An autosomal dominant disease characterized by
CC hypoplastic or absent tibia, and polydactyly.
CC {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The
CC gene represented in this entry is involved in disease pathogenesis.
CC Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-
CC regulatory element of SHH and result in abnormal, ectopic SHH
CC expression with pathological consequences.
CC {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.
CC -!- DISEASE: Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal
CC dominant disorder characterized by polysyndactyly of hands and/or feet,
CC mirror image duplication of the feet, nasal defects, and loss of
CC identity between fibula and tibia. Some patients do not have nasal
CC abnormalities (segmental Laurin-Sandrow syndrome).
CC {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry
CC is involved in disease pathogenesis. Abnormal SHH limb expression with
CC pathological consequences is caused by duplications (16-75 kb)
CC involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-
CC regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
CC -!- CAUTION: The several steps and mechanisms that permit controlled Shh
CC dispersion and gradient formation remain controversial. The ShhNC C-
CC terminal domain displays an autoproteolysis activity and a cholesterol
CC transferase activity resulting in the cleavage and covalent attachment
CC of a cholesterol moiety to the C-terminal of the newly generated N-
CC terminal fragment (ShhN). The protein is further modified by covalent
CC addition of palmitate at the N-terminal of ShhN, resulting to the dual-
CC lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane
CC where it forms multimers. Further solubilization and release from the
CC cell surface seem to be achieved through different mechanisms,
CC including the interaction with DISP1 and SCUBE2, movement by
CC lipoprotein particles, transport by cellular extensions called
CC cytonemes or by proteolytic removal of both terminal lipidated peptides
CC (PubMed:26875496). Once released, the fully processed Shh can signal
CC within embryonic tissues both at short and long-range.
CC {ECO:0000269|PubMed:24522195, ECO:0000303|PubMed:26875496,
CC ECO:0000305|PubMed:22677548, ECO:0000305|PubMed:22902404}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SHHID378.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/shh/";
CC ---------------------------------------------------------------------------
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DR EMBL; L38518; AAA62179.1; -; mRNA.
DR EMBL; AY422195; AAQ87879.1; -; Genomic_DNA.
DR EMBL; AC002484; AAB67604.1; -; Genomic_DNA.
DR EMBL; AC078834; AAS01990.1; -; Genomic_DNA.
DR EMBL; CH236954; EAL23913.1; -; Genomic_DNA.
DR CCDS; CCDS5942.1; -.
DR RefSeq; NP_000184.1; NM_000193.3.
DR PDB; 3HO5; X-ray; 3.01 A; H=29-197.
DR PDB; 3M1N; X-ray; 1.85 A; A/B=23-197.
DR PDB; 3MXW; X-ray; 1.83 A; A=29-197.
DR PDB; 6DMY; EM; 3.60 A; B=24-197.
DR PDB; 6E1H; EM; 3.50 A; C=24-197.
DR PDB; 6N7G; EM; 6.80 A; C/F=24-197.
DR PDB; 6N7H; EM; 3.60 A; C=24-197.
DR PDB; 6N7K; EM; 6.50 A; C/F=24-197.
DR PDB; 6OEV; EM; 3.80 A; C=24-197.
DR PDB; 6PJV; X-ray; 1.43 A; A=29-197.
DR PDB; 6RMG; EM; 3.40 A; B=21-197.
DR PDB; 6RVD; EM; 3.50 A; C=24-197.
DR PDB; 7E2I; EM; 4.07 A; G=1-462.
DR PDB; 7MHZ; EM; 3.20 A; B=24-31.
DR PDB; 7RHQ; EM; 3.53 A; C=24-197.
DR PDBsum; 3HO5; -.
DR PDBsum; 3M1N; -.
DR PDBsum; 3MXW; -.
DR PDBsum; 6DMY; -.
DR PDBsum; 6E1H; -.
DR PDBsum; 6N7G; -.
DR PDBsum; 6N7H; -.
DR PDBsum; 6N7K; -.
DR PDBsum; 6OEV; -.
DR PDBsum; 6PJV; -.
DR PDBsum; 6RMG; -.
DR PDBsum; 6RVD; -.
DR PDBsum; 7E2I; -.
DR PDBsum; 7MHZ; -.
DR PDBsum; 7RHQ; -.
DR AlphaFoldDB; Q15465; -.
DR SMR; Q15465; -.
DR BioGRID; 112365; 17.
DR DIP; DIP-61763N; -.
DR IntAct; Q15465; 3.
DR STRING; 9606.ENSP00000297261; -.
DR BindingDB; Q15465; -.
DR ChEMBL; CHEMBL5602; -.
DR DrugCentral; Q15465; -.
DR MEROPS; C46.002; -.
DR GlyGen; Q15465; 1 site.
DR iPTMnet; Q15465; -.
DR PhosphoSitePlus; Q15465; -.
DR SwissPalm; Q15465; -.
DR BioMuta; SHH; -.
DR DMDM; 6094283; -.
DR MassIVE; Q15465; -.
DR PaxDb; Q15465; -.
DR PeptideAtlas; Q15465; -.
DR PRIDE; Q15465; -.
DR ABCD; Q15465; 17 sequenced antibodies.
DR Antibodypedia; 4514; 596 antibodies from 41 providers.
DR DNASU; 6469; -.
DR Ensembl; ENST00000297261.7; ENSP00000297261.2; ENSG00000164690.8.
DR GeneID; 6469; -.
DR KEGG; hsa:6469; -.
DR MANE-Select; ENST00000297261.7; ENSP00000297261.2; NM_000193.4; NP_000184.1.
DR UCSC; uc003wmk.2; human.
DR CTD; 6469; -.
DR DisGeNET; 6469; -.
DR GeneCards; SHH; -.
DR GeneReviews; SHH; -.
DR HGNC; HGNC:10848; SHH.
DR HPA; ENSG00000164690; Tissue enhanced (adrenal gland, liver, stomach, urinary bladder).
DR MalaCards; SHH; -.
DR MIM; 135750; phenotype.
DR MIM; 142945; phenotype.
DR MIM; 147250; phenotype.
DR MIM; 174500; phenotype.
DR MIM; 188740; phenotype.
DR MIM; 600725; gene.
DR MIM; 611638; phenotype.
DR neXtProt; NX_Q15465; -.
DR OpenTargets; ENSG00000164690; -.
DR Orphanet; 485275; Acquired schizencephaly.
DR Orphanet; 93925; Alobar holoprosencephaly.
DR Orphanet; 476119; Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome.
DR Orphanet; 98938; Colobomatous microphthalmia.
DR Orphanet; 3332; Hypoplastic tibiae-postaxial polydactyly syndrome.
DR Orphanet; 93924; Lobar holoprosencephaly.
DR Orphanet; 280200; Microform holoprosencephaly.
DR Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly.
DR Orphanet; 93336; Polydactyly of a triphalangeal thumb.
DR Orphanet; 93321; Radial hemimelia.
DR Orphanet; 220386; Semilobar holoprosencephaly.
DR Orphanet; 280195; Septopreoptic holoprosencephaly.
DR Orphanet; 93405; Syndactyly type 4.
DR Orphanet; 2950; Triphalangeal thumb-polysyndactyly syndrome.
DR PharmGKB; PA35752; -.
DR VEuPathDB; HostDB:ENSG00000164690; -.
DR eggNOG; KOG3638; Eukaryota.
DR GeneTree; ENSGT00940000159119; -.
DR HOGENOM; CLU_034686_0_0_1; -.
DR InParanoid; Q15465; -.
DR OMA; LDSHSIH; -.
DR OrthoDB; 1169356at2759; -.
DR PhylomeDB; Q15465; -.
DR TreeFam; TF106458; -.
DR PathwayCommons; Q15465; -.
DR Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR Reactome; R-HSA-5358346; Hedgehog ligand biogenesis.
DR Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD.
DR Reactome; R-HSA-5362798; Release of Hh-Np from the secreting cell.
DR Reactome; R-HSA-5632681; Ligand-receptor interactions.
DR Reactome; R-HSA-5632684; Hedgehog 'on' state.
DR Reactome; R-HSA-5635838; Activation of SMO.
DR Reactome; R-HSA-5658034; HHAT G278V doesn't palmitoylate Hh-Np.
DR SignaLink; Q15465; -.
DR SIGNOR; Q15465; -.
DR BioGRID-ORCS; 6469; 12 hits in 1073 CRISPR screens.
DR ChiTaRS; SHH; human.
DR EvolutionaryTrace; Q15465; -.
DR GeneWiki; Sonic_hedgehog; -.
DR GenomeRNAi; 6469; -.
DR Pharos; Q15465; Tchem.
DR PRO; PR:Q15465; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q15465; protein.
DR Bgee; ENSG00000164690; Expressed in right lobe of liver and 99 other tissues.
DR ExpressionAtlas; Q15465; baseline and differential.
DR Genevisible; Q15465; HS.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; TAS:Reactome.
DR GO; GO:0005539; F:glycosaminoglycan binding; IEA:Ensembl.
DR GO; GO:0043237; F:laminin-1 binding; ISS:UniProtKB.
DR GO; GO:0016015; F:morphogen activity; TAS:ParkinsonsUK-UCL.
DR GO; GO:0005113; F:patched binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0046632; P:alpha-beta T cell differentiation; IEA:Ensembl.
DR GO; GO:0008209; P:androgen metabolic process; ISS:UniProtKB.
DR GO; GO:0048645; P:animal organ formation; IEA:Ensembl.
DR GO; GO:0097190; P:apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0060840; P:artery development; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR GO; GO:0060020; P:Bergmann glial cell differentiation; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; IEA:Ensembl.
DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; ISS:UniProtKB.
DR GO; GO:0060445; P:branching involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; ISS:UniProtKB.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; ISS:UniProtKB.
DR GO; GO:0060447; P:bud outgrowth involved in lung branching; IEA:Ensembl.
DR GO; GO:0043010; P:camera-type eye development; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0043369; P:CD4-positive or CD8-positive, alpha-beta T cell lineage commitment; IDA:BHF-UCL.
DR GO; GO:0048468; P:cell development; ISS:UniProtKB.
DR GO; GO:0001708; P:cell fate specification; ISS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; ISS:UniProtKB.
DR GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl.
DR GO; GO:0007417; P:central nervous system development; ISS:UniProtKB.
DR GO; GO:0021930; P:cerebellar granule cell precursor proliferation; ISS:UniProtKB.
DR GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; ISS:BHF-UCL.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR GO; GO:0009953; P:dorsal/ventral pattern formation; ISS:UniProtKB.
DR GO; GO:0007398; P:ectoderm development; IEA:Ensembl.
DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; IEA:Ensembl.
DR GO; GO:0042733; P:embryonic digit morphogenesis; ISS:UniProtKB.
DR GO; GO:0048617; P:embryonic foregut morphogenesis; IEA:Ensembl.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; IEA:Ensembl.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:0030326; P:embryonic limb morphogenesis; ISS:UniProtKB.
DR GO; GO:0009880; P:embryonic pattern specification; TAS:BHF-UCL.
DR GO; GO:0048706; P:embryonic skeletal system development; IEA:Ensembl.
DR GO; GO:0006897; P:endocytosis; IEA:Ensembl.
DR GO; GO:0060767; P:epithelial cell proliferation involved in prostate gland development; IEA:Ensembl.
DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0060738; P:epithelial-mesenchymal signaling involved in prostate gland development; IDA:MGI.
DR GO; GO:0090162; P:establishment of epithelial cell polarity; IEA:Ensembl.
DR GO; GO:0030900; P:forebrain development; ISS:UniProtKB.
DR GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
DR GO; GO:0031069; P:hair follicle morphogenesis; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0001947; P:heart looping; ISS:BHF-UCL.
DR GO; GO:0030902; P:hindbrain development; ISS:UniProtKB.
DR GO; GO:0007442; P:hindgut morphogenesis; IEA:Ensembl.
DR GO; GO:0048839; P:inner ear development; IEA:Ensembl.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0045109; P:intermediate filament organization; IEA:Ensembl.
DR GO; GO:0060459; P:left lung development; IEA:Ensembl.
DR GO; GO:0060174; P:limb bud formation; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; ISS:UniProtKB.
DR GO; GO:0060428; P:lung epithelium development; IEA:Ensembl.
DR GO; GO:0060463; P:lung lobe morphogenesis; IEA:Ensembl.
DR GO; GO:0060484; P:lung-associated mesenchyme development; IEA:Ensembl.
DR GO; GO:0002320; P:lymphoid progenitor cell differentiation; IMP:BHF-UCL.
DR GO; GO:0030539; P:male genitalia development; ISS:UniProtKB.
DR GO; GO:0097152; P:mesenchymal cell apoptotic process; IEA:Ensembl.
DR GO; GO:0060916; P:mesenchymal cell proliferation involved in lung development; IEA:Ensembl.
DR GO; GO:0060783; P:mesenchymal smoothened signaling pathway involved in prostate gland development; IEA:Ensembl.
DR GO; GO:0072205; P:metanephric collecting duct development; IEP:UniProtKB.
DR GO; GO:0072136; P:metanephric mesenchymal cell proliferation involved in metanephros development; ISS:UniProtKB.
DR GO; GO:0001656; P:metanephros development; ISS:UniProtKB.
DR GO; GO:0030901; P:midbrain development; ISS:UniProtKB.
DR GO; GO:0045445; P:myoblast differentiation; IEA:Ensembl.
DR GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0045596; P:negative regulation of cell differentiation; ISS:UniProtKB.
DR GO; GO:0030336; P:negative regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0090370; P:negative regulation of cholesterol efflux; ISS:BHF-UCL.
DR GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; IEA:Ensembl.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:2000357; P:negative regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IEA:Ensembl.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0033085; P:negative regulation of T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:2000062; P:negative regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:0045060; P:negative thymic T cell selection; ISS:UniProtKB.
DR GO; GO:0001755; P:neural crest cell migration; ISS:UniProtKB.
DR GO; GO:0007405; P:neuroblast proliferation; ISS:UniProtKB.
DR GO; GO:0048663; P:neuron fate commitment; ISS:UniProtKB.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0014003; P:oligodendrocyte development; IEA:Ensembl.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IBA:GO_Central.
DR GO; GO:0002076; P:osteoblast development; IEA:Ensembl.
DR GO; GO:0031016; P:pancreas development; IEA:Ensembl.
DR GO; GO:0007389; P:pattern specification process; ISS:UniProtKB.
DR GO; GO:0009949; P:polarity specification of anterior/posterior axis; ISS:UniProtKB.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; ISS:UniProtKB.
DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; IEA:Ensembl.
DR GO; GO:0051781; P:positive regulation of cell division; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0060769; P:positive regulation of epithelial cell proliferation involved in prostate gland development; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0007228; P:positive regulation of hh target transcription factor activity; ISS:BHF-UCL.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; ISS:BHF-UCL.
DR GO; GO:2000358; P:positive regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:2000729; P:positive regulation of mesenchymal cell proliferation involved in ureter development; ISS:UniProtKB.
DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IEA:Ensembl.
DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IEA:Ensembl.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IEA:Ensembl.
DR GO; GO:0061189; P:positive regulation of sclerotome development; IDA:BHF-UCL.
DR GO; GO:0014858; P:positive regulation of skeletal muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IEA:Ensembl.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IDA:UniProtKB.
DR GO; GO:0051155; P:positive regulation of striated muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:2000063; P:positive regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0045059; P:positive thymic T cell selection; ISS:UniProtKB.
DR GO; GO:0060516; P:primary prostatic bud elongation; IEA:Ensembl.
DR GO; GO:0060523; P:prostate epithelial cord elongation; IEA:Ensembl.
DR GO; GO:0030850; P:prostate gland development; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR GO; GO:0060251; P:regulation of glial cell proliferation; IEA:Ensembl.
DR GO; GO:0060782; P:regulation of mesenchymal cell proliferation involved in prostate gland development; IEA:Ensembl.
DR GO; GO:1900175; P:regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry; NAS:BHF-UCL.
DR GO; GO:0042481; P:regulation of odontogenesis; ISS:BHF-UCL.
DR GO; GO:0060685; P:regulation of prostatic bud formation; IEA:Ensembl.
DR GO; GO:1900180; P:regulation of protein localization to nucleus; IDA:BHF-UCL.
DR GO; GO:0030162; P:regulation of proteolysis; ISS:UniProtKB.
DR GO; GO:0072091; P:regulation of stem cell proliferation; IEA:Ensembl.
DR GO; GO:0060458; P:right lung development; IEA:Ensembl.
DR GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
DR GO; GO:0060662; P:salivary gland cavitation; IEA:Ensembl.
DR GO; GO:0014856; P:skeletal muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0098528; P:skeletal muscle fiber differentiation; IEA:Ensembl.
DR GO; GO:0048745; P:smooth muscle tissue development; IEP:UniProtKB.
DR GO; GO:0007224; P:smoothened signaling pathway; IDA:FlyBase.
DR GO; GO:0021938; P:smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation; IEA:Ensembl.
DR GO; GO:0061053; P:somite development; ISS:BHF-UCL.
DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IEA:Ensembl.
DR GO; GO:0021522; P:spinal cord motor neuron differentiation; IEA:Ensembl.
DR GO; GO:0048864; P:stem cell development; ISS:UniProtKB.
DR GO; GO:0072089; P:stem cell proliferation; IEA:Ensembl.
DR GO; GO:0014706; P:striated muscle tissue development; IEA:Ensembl.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:BHF-UCL.
DR GO; GO:0042098; P:T cell proliferation; IEA:Ensembl.
DR GO; GO:0021978; P:telencephalon regionalization; IEA:Ensembl.
DR GO; GO:0021794; P:thalamus development; IEA:Ensembl.
DR GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl.
DR GO; GO:0060439; P:trachea morphogenesis; IEA:Ensembl.
DR GO; GO:1905327; P:tracheoesophageal septum formation; IEA:Ensembl.
DR GO; GO:0036484; P:trunk neural crest cell migration; IEA:Ensembl.
DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
DR GO; GO:0007418; P:ventral midline development; TAS:BHF-UCL.
DR Gene3D; 3.30.1380.10; -; 1.
DR InterPro; IPR001657; Hedgehog.
DR InterPro; IPR001767; Hedgehog_Hint.
DR InterPro; IPR009045; Hedgehog_sig/DD-Pept_Zn-bd_sf.
DR InterPro; IPR000320; Hedgehog_signalling_dom.
DR InterPro; IPR003586; Hint_dom_C.
DR InterPro; IPR003587; Hint_dom_N.
DR InterPro; IPR036844; Hint_dom_sf.
DR InterPro; IPR006141; Intein_N.
DR Pfam; PF01085; HH_signal; 1.
DR Pfam; PF01079; Hint; 1.
DR PIRSF; PIRSF009400; Peptidase_C46; 1.
DR PRINTS; PR00632; SONICHHOG.
DR SMART; SM00305; HintC; 1.
DR SMART; SM00306; HintN; 1.
DR SUPFAM; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 1.
DR PROSITE; PS50817; INTEIN_N_TER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Autocatalytic cleavage; Calcium; Cell membrane;
KW Developmental protein; Direct protein sequencing; Disease variant;
KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Holoprosencephaly;
KW Hydrolase; Lipoprotein; Membrane; Metal-binding; Microphthalmia; Palmitate;
KW Protease; Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..23
FT /evidence="ECO:0000269|PubMed:9593755"
FT CHAIN 24..462
FT /note="Sonic hedgehog protein"
FT /id="PRO_0000013208"
FT CHAIN 24..197
FT /note="Sonic hedgehog protein N-product"
FT /id="PRO_0000013209"
FT REGION 279..302
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 395..414
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 32..38
FT /note="Cardin-Weintraub"
FT /evidence="ECO:0000269|PubMed:23118222"
FT BINDING 89
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 95
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 125
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 129
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 131
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:20504762,
FT ECO:0007744|PDB:3MXW"
FT BINDING 140
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10753901,
FT ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT ECO:0007744|PDB:3MXW"
FT BINDING 147
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10753901,
FT ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT ECO:0007744|PDB:3MXW"
FT BINDING 182
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:10753901,
FT ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT ECO:0007744|PDB:3MXW"
FT SITE 197..198
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 243
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 267
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 270
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 24
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:18534984,
FT ECO:0000269|PubMed:31875564, ECO:0000269|PubMed:9593755"
FT LIPID 197
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
FT CARBOHYD 278
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT VARIANT 6
FT /note="R -> T (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023804"
FT VARIANT 17
FT /note="L -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062592"
FT VARIANT 26
FT /note="P -> L (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062593"
FT VARIANT 27
FT /note="G -> A (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15107988,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039888"
FT VARIANT 31
FT /note="G -> R (in HPE3; the same mutation in the mouse
FT sequence introduces a cleavage site for a furin-like
FT protease resulting in abnormal protein processing; cleavage
FT at this site removes 11 amino acids from the N-terminal
FT domain and reduces affinity of Shh for Ptch1 and signaling
FT potency in assays using chicken embryo neural plate
FT explants and mouse C3H10T1/2 stem cells; dbSNP:rs28936675)"
FT /evidence="ECO:0000269|PubMed:16282375,
FT ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_003619"
FT VARIANT 39
FT /note="L -> P (in HPE3; dbSNP:rs1428916820)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062594"
FT VARIANT 53
FT /note="E -> K (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062595"
FT VARIANT 83
FT /note="D -> V (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062596"
FT VARIANT 84
FT /note="I -> F (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062597"
FT VARIANT 88
FT /note="D -> V (in HPE3; familial; the same mutation in the
FT mouse sequence moderately reduces Ptch1 binding in vitro
FT and signaling potency in chicken embryo neural plate
FT explant assays compared with wild-type sequence;
FT dbSNP:rs104894050)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:19603532"
FT /id="VAR_009163"
FT VARIANT 100
FT /note="Q -> H (in HPE3; sporadic; in the mouse sequence
FT does not affect signaling activity in any of Shh signaling
FT assays and causes no apparent defects in cholesterol-
FT mediated autoprocessing reactions; dbSNP:rs587778792)"
FT /evidence="ECO:0000269|PubMed:10441331,
FT ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:16282375,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009164"
FT VARIANT 102
FT /note="C -> R (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062598"
FT VARIANT 102
FT /note="C -> Y (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062599"
FT VARIANT 106..107
FT /note="Missing (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023805"
FT VARIANT 109
FT /note="L -> F (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062600"
FT VARIANT 110
FT /note="A -> D (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023806"
FT VARIANT 110
FT /note="A -> T (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062601"
FT VARIANT 111
FT /note="I -> F (in SMMCI; dbSNP:rs104894049)"
FT /evidence="ECO:0000269|PubMed:11471164,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_017883"
FT VARIANT 111
FT /note="I -> N (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15942952,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039889"
FT VARIANT 115
FT /note="N -> K (in HPE3; familial; in the mouse sequence
FT shows no change in activities at different temperatures;
FT dbSNP:rs267607047)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:19603532"
FT /id="VAR_009165"
FT VARIANT 117
FT /note="W -> G (in HPE3; the same mutation in the mouse
FT sequence causes a failure of Shh processing leading to
FT retention of the immature glycosylated protein within the
FT endoplasmic reticulum of transfected cells; causes a
FT temperature-dependent conformational change that allows Shh
FT to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT degrees Celsius; the mutation drastically reduces signaling
FT potency in chicken embryo neural plate explant assays;
FT dbSNP:rs104894040)"
FT /evidence="ECO:0000269|PubMed:16282375,
FT ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_003620"
FT VARIANT 117
FT /note="W -> R (in HPE3; the same mutation in the mouse
FT sequence causes a failure of Shh processing leading to
FT retention of the immature glycosylated protein within the
FT endoplasmic reticulum of transfected cells; causes a
FT temperature-dependent conformational change that allows Shh
FT to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT degrees Celsius; drastically reduces signaling potency in
FT chicken embryo neural plate explant assays;
FT dbSNP:rs104894040)"
FT /evidence="ECO:0000269|PubMed:16282375,
FT ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_003621"
FT VARIANT 124
FT /note="V -> M (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062602"
FT VARIANT 136
FT /note="E -> K (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062603"
FT VARIANT 140
FT /note="H -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:11479728,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039890"
FT VARIANT 140
FT /note="H -> Q (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15942953,
FT ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532"
FT /id="VAR_039891"
FT VARIANT 143
FT /note="G -> D (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062604"
FT VARIANT 144
FT /note="R -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062605"
FT VARIANT 147
FT /note="D -> N (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062606"
FT VARIANT 150
FT /note="T -> K (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062607"
FT VARIANT 150
FT /note="T -> R (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023807"
FT VARIANT 156
FT /note="S -> R (in HPE3; dbSNP:rs1554494372)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062608"
FT VARIANT 170
FT /note="F -> C (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062609"
FT VARIANT 171
FT /note="D -> H (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062610"
FT VARIANT 176..178
FT /note="Missing (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023808"
FT VARIANT 183
FT /note="C -> F (in HPE3)"
FT /evidence="ECO:0000269|PubMed:11479728,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039892"
FT VARIANT 183
FT /note="C -> R (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062611"
FT VARIANT 183
FT /note="C -> Y (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062612"
FT VARIANT 184
FT /note="S -> L (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062613"
FT VARIANT 188
FT /note="E -> Q (in HPE3; familial; dbSNP:rs587778799)"
FT /evidence="ECO:0000269|PubMed:10441331,
FT ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:16282375,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009166"
FT VARIANT 196..200
FT /note="Missing (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062614"
FT VARIANT 196
FT /note="G -> E (in HPE3; dbSNP:rs752650571)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062615"
FT VARIANT 197
FT /note="G -> V (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062616"
FT VARIANT 198
FT /note="C -> F (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062617"
FT VARIANT 198
FT /note="C -> S (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062618"
FT VARIANT 218
FT /note="L -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:17001669,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_062619"
FT VARIANT 222
FT /note="D -> N (in HPE3; familial; dbSNP:rs587778805)"
FT /evidence="ECO:0000269|PubMed:10441331,
FT ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:19603532"
FT /id="VAR_009167"
FT VARIANT 224
FT /note="V -> E (in HPE3; dbSNP:rs104894042)"
FT /evidence="ECO:0000269|PubMed:19603532,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_009168"
FT VARIANT 226
FT /note="A -> T (in HPE3; familial; dbSNP:rs104894043)"
FT /evidence="ECO:0000269|PubMed:19603532,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_009169"
FT VARIANT 231
FT /note="G -> V (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062620"
FT VARIANT 232
FT /note="R -> G (in HPE3; dbSNP:rs1347054935)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062621"
FT VARIANT 234
FT /note="L -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062622"
FT VARIANT 236
FT /note="S -> N (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062623"
FT VARIANT 236
FT /note="S -> R (in HPE3; familial; dbSNP:rs587778806)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009170"
FT VARIANT 241
FT /note="F -> L (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062624"
FT VARIANT 241
FT /note="F -> V (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062625"
FT VARIANT 255
FT /note="I -> N (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062626"
FT VARIANT 263..269
FT /note="Missing (in HPE3; sporadic)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009171"
FT VARIANT 267
FT /note="T -> I (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15107988,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039893"
FT VARIANT 271
FT /note="L -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023809"
FT VARIANT 275
FT /note="A -> E (in HPE3; dbSNP:rs556192490)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062627"
FT VARIANT 280
FT /note="S -> W (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062628"
FT VARIANT 290
FT /note="G -> D (in HPE3; sporadic; dbSNP:rs104894047)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009172"
FT VARIANT 296
FT /note="G -> A (in HPE3; unknown pathological significance;
FT dbSNP:rs955894039)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062629"
FT VARIANT 310
FT /note="R -> C (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062630"
FT VARIANT 321
FT /note="R -> S (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062631"
FT VARIANT 332
FT /note="V -> A (in HPE3 and SMMCI; dbSNP:rs104894052)"
FT /evidence="ECO:0000269|PubMed:15103725,
FT ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:19603532"
FT /id="VAR_023810"
FT VARIANT 346
FT /note="A -> V (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062632"
FT VARIANT 347
FT /note="P -> L (in HPE3; dbSNP:rs886042458)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062633"
FT VARIANT 347
FT /note="P -> Q (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023811"
FT VARIANT 347
FT /note="P -> R (in HPE3; dbSNP:rs886042458)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062634"
FT VARIANT 354
FT /note="I -> T (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023812"
FT VARIANT 362
FT /note="S -> L (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062635"
FT VARIANT 363
FT /note="C -> Y (in HPE3)"
FT /evidence="ECO:0000269|PubMed:17001669,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_062636"
FT VARIANT 364
FT /note="Y -> C (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062637"
FT VARIANT 373
FT /note="A -> T (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15107988,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_039894"
FT VARIANT 374
FT /note="H -> R (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062638"
FT VARIANT 376
FT /note="A -> D (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062639"
FT VARIANT 377
FT /note="F -> S (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062640"
FT VARIANT 378..380
FT /note="Missing (in HPE3; familial)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_009173"
FT VARIANT 381
FT /note="R -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:15221788,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_023813"
FT VARIANT 382
FT /note="L -> P (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062641"
FT VARIANT 383
FT /note="A -> T (in HPE3; sporadic; dbSNP:rs137853341)"
FT /evidence="ECO:0000269|PubMed:19603532,
FT ECO:0000269|PubMed:9302262"
FT /id="VAR_009174"
FT VARIANT 391
FT /note="A -> T (in HPE3; unknown pathological significance;
FT dbSNP:rs1131692264)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062642"
FT VARIANT 401..408
FT /note="Missing (in ocular coloboma)"
FT /evidence="ECO:0000269|PubMed:12503095"
FT /id="VAR_017884"
FT VARIANT 402..409
FT /note="Missing (in HPE3; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062643"
FT VARIANT 404..408
FT /note="Missing (in HPE3; familial)"
FT /id="VAR_009175"
FT VARIANT 405..409
FT /note="Missing (in HPE3; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062644"
FT VARIANT 411
FT /note="G -> GG (in HPE3; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062645"
FT VARIANT 416
FT /note="T -> A (in HPE3; unknown pathological significance;
FT dbSNP:rs1412744230)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062646"
FT VARIANT 424
FT /note="P -> A (in HPE3; familial; dbSNP:rs104894048)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009176"
FT VARIANT 435
FT /note="Y -> N (in HPE3)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062647"
FT VARIANT 436
FT /note="S -> L (in HPE3; sporadic)"
FT /evidence="ECO:0000269|PubMed:10556296,
FT ECO:0000269|PubMed:19603532"
FT /id="VAR_009177"
FT VARIANT 456
FT /note="G -> R (in HPE3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:19603532"
FT /id="VAR_062648"
FT MUTAGEN 24
FT /note="C->S,A: Abolishes palmitoylation."
FT /evidence="ECO:0000269|PubMed:18534984,
FT ECO:0000269|PubMed:31875564, ECO:0000269|PubMed:9593755"
FT STRAND 30..32
FT /evidence="ECO:0007829|PDB:3M1N"
FT STRAND 47..51
FT /evidence="ECO:0007829|PDB:6PJV"
FT TURN 56..59
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 71..74
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 84..86
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 91..93
FT /evidence="ECO:0007829|PDB:3MXW"
FT HELIX 94..96
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 100..116
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 122..126
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 139..141
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 145..150
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 155..157
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 158..167
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 171..177
FT /evidence="ECO:0007829|PDB:6PJV"
FT STRAND 180..184
FT /evidence="ECO:0007829|PDB:6PJV"
FT HELIX 188..190
FT /evidence="ECO:0007829|PDB:3MXW"
SQ SEQUENCE 462 AA; 49607 MW; DD687AFA582A4749 CRC64;
MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN VAEKTLGASG
RYEGKISRNS ERFKELTPNY NPDIIFKDEE NTGADRLMTQ RCKDKLNALA ISVMNQWPGV
KLRVTEGWDE DGHHSEESLH YEGRAVDITT SDRDRSKYGM LARLAVEAGF DWVYYESKAH
IHCSVKAENS VAAKSGGCFP GSATVHLEQG GTKLVKDLSP GDRVLAADDQ GRLLYSDFLT
FLDRDDGAKK VFYVIETREP RERLLLTAAH LLFVAPHNDS ATGEPEASSG SGPPSGGALG
PRALFASRVR PGQRVYVVAE RDGDRRLLPA AVHSVTLSEE AAGAYAPLTA QGTILINRVL
ASCYAVIEEH SWAHRAFAPF RLAHALLAAL APARTDRGGD SGGGDRGGGG GRVALTAPGA
ADAPGAGATA GIHWYSQLLY QIGTWLLDSE ALHPLGMAVK SS
