SHH_XENLA
ID SHH_XENLA Reviewed; 444 AA.
AC Q92000; Q91894;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Sonic hedgehog protein {ECO:0000305};
DE Short=SHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000250|UniProtKB:Q62226};
DE Short=ShhNC {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=VHH-1;
DE AltName: Full=X-SHH;
DE Contains:
DE RecName: Full=Sonic hedgehog protein N-product;
DE Short=ShhN;
DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000250|UniProtKB:Q62226};
DE Short=ShhNp {ECO:0000250|UniProtKB:Q62226};
DE Flags: Precursor;
GN Name=shh {ECO:0000250|UniProtKB:Q15465};
OS Xenopus laevis (African clawed frog).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Amphibia;
OC Batrachia; Anura; Pipoidea; Pipidae; Xenopodinae; Xenopus; Xenopus.
OX NCBI_TaxID=8355;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL
RP STAGE, AND INDUCTION.
RC TISSUE=Intestine;
RX PubMed=7630736; DOI=10.1093/nar/23.13.2555;
RA Stolow M.A., Shi Y.-B.;
RT "Xenopus sonic hedgehog as a potential morphogen during embryogenesis and
RT thyroid hormone-dependent metamorphosis.";
RL Nucleic Acids Res. 23:2555-2562(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
RC TISSUE=Embryo;
RX PubMed=7671800; DOI=10.1242/dev.121.8.2337;
RA Ekker S.C., McGrew L.L., Lai C.-J., Lee J.J., von Kessler D.P., Moon R.T.,
RA Beachy P.A.;
RT "Distinct expression and shared activities of members of the hedgehog gene
RT family of Xenopus laevis.";
RL Development 121:2337-2347(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
RC TISSUE=Notochord;
RX PubMed=7551564; DOI=10.1006/mcne.1995.1011;
RA Ruiz i Altaba A., Jessell T.M., Roelink H.;
RT "Restrictions to floor plate induction by hedgehog and winged-helix genes
RT in the neural tube of frog embryos.";
RL Mol. Cell. Neurosci. 6:106-121(1995).
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:Q15465, 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 (By
CC similarity). Involved in the patterning of the anterior-posterior axis
CC of the developing limb bud (By similarity). Essential for axon guidance
CC (By similarity). Binds to the patched (PTCH1) receptor, which functions
CC in association with smoothened (SMO), to activate the transcription of
CC target genes (By similarity). In the absence of SHH, PTCH1 represses
CC the constitutive signaling activity of SMO (By similarity).
CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:7551564, ECO:0000269|PubMed:7630736,
CC ECO:0000269|PubMed:7671800}.
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: 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 (By
CC similarity). Interacts with DISP1 via its cholesterol anchor (By
CC similarity). Interacts with SCUBE2 (By similarity).
CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}.
CC -!- SUBUNIT: [Sonic hedgehog protein N-product]: Multimer.
CC {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in the ER
CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
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 (By similarity). Further solubilization and release
CC from the 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 the proteolytic removal of both terminal lipidated
CC peptides. {ECO:0000250|UniProtKB:Q62226}.
CC -!- TISSUE SPECIFICITY: Strongly expressed in notochord and neural floor
CC plate during embryogenesis. In tadpole, high expression is observed in
CC pancreas/stomach, moderate expression in tail, and low expression in
CC intestine, brain, and hind limb. {ECO:0000269|PubMed:7551564,
CC ECO:0000269|PubMed:7630736, ECO:0000269|PubMed:7671800}.
CC -!- DEVELOPMENTAL STAGE: First detected at the neurula (stages 16-17).
CC First peak of expression around tadpole hatching (stages 33-40). High
CC expression observed in intestine at the climax of morphogenesis (stages
CC 60-62) when intestine epithelial undergoes morphogenesis.
CC {ECO:0000269|PubMed:7551564, ECO:0000269|PubMed:7630736,
CC ECO:0000269|PubMed:7671800}.
CC -!- INDUCTION: By thyroid hormone. {ECO:0000269|PubMed:7630736}.
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:0000250|UniProtKB:Q62226}.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW)
CC motif is required for heparan sulfate binding of the solubilized ShhNp
CC (By similarity). The N-terminal palmitoylated peptide is cleaved at the
CC Heparan sulfate-binding Cardin-Weintraub (CW) motif site (By
CC similarity). The cleavage reduced the interactions with heparan
CC sulfate. The cleavage is enhanced by SCUBE2 (By similarity).
CC {ECO:0000250|UniProtKB:Q62226}.
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 (By
CC similarity). ShhN is the active species in both local and long-range
CC signaling, whereas the C-product (ShhC) is degraded in the reticulum
CC endoplasmic (By similarity). {ECO:0000250|UniProtKB:Q62226}.
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 (By similarity). {ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C-
CC terminal peptides of ShhNp can be cleaved (shedding) (By similarity).
CC The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub
CC (CW) motif site (By similarity). The cleavage reduced the interactions
CC with heparan sulfate (By similarity). The cleavage is enhanced by
CC SCUBE2 (By similarity). {ECO:0000250|UniProtKB:Q62226}.
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
CC peptides. Once released, the fully processed Shh can signal within
CC embryonic tissues both at short and long-range.
CC {ECO:0000250|UniProtKB:Q62226}.
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DR EMBL; L39213; AAC42227.1; -; mRNA.
DR EMBL; U26314; AAA85162.1; -; mRNA.
DR EMBL; L35248; AAA49981.1; -; mRNA.
DR PIR; S56765; S56765.
DR RefSeq; NP_001081782.1; NM_001088313.1.
DR AlphaFoldDB; Q92000; -.
DR SMR; Q92000; -.
DR MEROPS; C46.002; -.
DR PRIDE; Q92000; -.
DR GeneID; 398047; -.
DR KEGG; xla:398047; -.
DR CTD; 398047; -.
DR Xenbase; XB-GENE-864913; shh.L.
DR OMA; HQVDLQS; -.
DR OrthoDB; 1169356at2759; -.
DR Proteomes; UP000186698; Chromosome 6L.
DR Bgee; 398047; Expressed in lung and 8 other tissues.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0048731; P:system development; IEA:UniProt.
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 2: Evidence at transcript level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Palmitate; Protease; Reference proteome; Repeat; Signal;
KW Zinc.
FT SIGNAL 1..24
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT CHAIN 25..444
FT /note="Sonic hedgehog protein"
FT /id="PRO_0000013220"
FT CHAIN 25..198
FT /note="Sonic hedgehog protein N-product"
FT /id="PRO_0000013221"
FT REPEAT 386..393
FT /note="1"
FT REPEAT 394..401
FT /note="2"
FT REPEAT 403..409
FT /note="3"
FT REGION 386..409
FT /note="3 X 8 AA tandem repeats of Q-V-D-L-Q-S-H-H"
FT MOTIF 33..39
FT /note="Cardin-Weintraub"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 96
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 130
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 148
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT SITE 198..199
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 244
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 266
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 269
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 25
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 198
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
FT CONFLICT 5..9
FT /note="TQSLL -> NSNLCW (in Ref. 3; AAA49981)"
FT /evidence="ECO:0000305"
FT CONFLICT 302..319
FT /note="DPKTMTLKAVKVEKVDLE -> ESQDHDLEGRGKWRRLILR (in Ref.
FT 3; AAA49981)"
FT /evidence="ECO:0000305"
FT CONFLICT 432
FT /note="N -> S (in Ref. 3; AAA49981)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 444 AA; 49453 MW; 73B4E4932FA2EFF2 CRC64;
MLVATQSLLL LSFICTLVTP PGLACGPGRG IGKRRHPKKL TPLAYKQFIP NVAEKTLGAS
GRYEGKITRN SDCFKELTPN YNPDIMFKDE ESTGADRLMT QRCKDKLNAL AISVMNQWPG
VKLRVTEGWD EDGHHLEESL HYEGRAVDIT TSDRDRSKYG MLGRLAVEAG FDWVYYESKA
HIHCSVKAEN SVAAKSGGCF PAGARVMVEF GGTKAVKDLR PGDRVLSSDP QGNLLYSDFL
MFIDQERDVK KLFYVIETSQ RKIRLTAAHL LFVAQTKVNG TRSFKSVFAS NIQPGDLIYT
ADPKTMTLKA VKVEKVDLEE DTGAYAPLTA HGTVVIDQVL ASCYAVIEEH TWAHLAFAPL
RFGMSLSSYI YPRDSSPPSG LQPHHQVDLQ SHHQVDLQSH HQVDLQSHHQ LEGIHWYSQL
LYQIGTWLLD SNSLHPLGMA TKSS
