GDF5_HUMAN
ID GDF5_HUMAN Reviewed; 501 AA.
AC P43026; E1P5Q2; Q96SB1;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 23-FEB-2022, sequence version 4.
DT 03-AUG-2022, entry version 217.
DE RecName: Full=Growth/differentiation factor 5;
DE Short=GDF-5;
DE AltName: Full=Bone morphogenetic protein 14;
DE Short=BMP-14;
DE AltName: Full=Cartilage-derived morphogenetic protein 1;
DE Short=CDMP-1;
DE AltName: Full=Lipopolysaccharide-associated protein 4;
DE Short=LAP-4;
DE Short=LPS-associated protein 4;
DE AltName: Full=Radotermin;
DE Flags: Precursor;
GN Name=GDF5; Synonyms=BMP14, CDMP1;
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 [GENOMIC DNA], AND VARIANT SER-276.
RC TISSUE=Placenta;
RX PubMed=7980526; DOI=10.1006/bbrc.1994.2508;
RA Hoetten G., Neidhardt H., Jacobowsky B., Pohl J.;
RT "Cloning and expression of recombinant human growth/differentiation factor
RT 5.";
RL Biochem. Biophys. Res. Commun. 204:646-652(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Articular cartilage;
RX PubMed=7961761; DOI=10.1016/s0021-9258(18)46918-9;
RA Chang S., Hoang B., Thomas J.T., Vukicevic S., Luyten F.P., Ryba N.J.P.,
RA Kozak C.A., Reddi A.H., Moos M.;
RT "Cartilage-derived morphogenetic proteins. New members of the transforming
RT growth factor-beta superfamily predominantly expressed in long bones during
RT human embryonic development.";
RL J. Biol. Chem. 269:28227-28234(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-276.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INVOLVEMENT IN AMD2C.
RX PubMed=8589725; DOI=10.1038/ng0396-315;
RA Thomas J.T., Lin K., Nandedkar M., Camargo M., Cervenka J., Luyten F.P.;
RT "A human chondrodysplasia due to a mutation in a TGF-beta superfamily
RT member.";
RL Nat. Genet. 12:315-317(1996).
RN [7]
RP FUNCTION, IDENTIFICATION AS LPS RECEPTOR, INTERACTION WITH CXCR4; HSP90AA1
RP AND HSPA8, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=11276205; DOI=10.1038/86342;
RA Triantafilou K., Triantafilou M., Dedrick R.L.;
RT "A CD14-independent LPS receptor cluster.";
RL Nat. Immunol. 2:338-345(2001).
RN [8]
RP FUNCTION.
RX PubMed=15530414; DOI=10.1016/j.bbrc.2004.10.055;
RA Bai X., Xiao Z., Pan Y., Hu J., Pohl J., Wen J., Li L.;
RT "Cartilage-derived morphogenetic protein-1 promotes the differentiation of
RT mesenchymal stem cells into chondrocytes.";
RL Biochem. Biophys. Res. Commun. 325:453-460(2004).
RN [9]
RP INTERACTION WITH FBN1 AND FBN2.
RX PubMed=18339631; DOI=10.1074/jbc.m707820200;
RA Sengle G., Charbonneau N.L., Ono R.N., Sasaki T., Alvarez J., Keene D.R.,
RA Baechinger H.P., Sakai L.Y.;
RT "Targeting of bone morphogenetic protein growth factor complexes to
RT fibrillin.";
RL J. Biol. Chem. 283:13874-13888(2008).
RN [10]
RP INTERACTION WITH NOG, FUNCTION, VARIANTS SYNS2 LYS-445 AND THR-445, AND
RP CHARACTERIZATION OF VARIANT SYNS2 THR-445.
RX PubMed=19956691; DOI=10.1371/journal.pgen.1000747;
RA Seemann P., Brehm A., Koenig J., Reissner C., Stricker S., Kuss P.,
RA Haupt J., Renninger S., Nickel J., Sebald W., Groppe J.C., Ploeger F.,
RA Pohl J., Schmidt-von Kegler M., Walther M., Gassner I., Rusu C.,
RA Janecke A.R., Dathe K., Mundlos S.;
RT "Mutations in GDF5 reveal a key residue mediating BMP inhibition by
RT NOGGIN.";
RL PLoS Genet. 5:E1000747-E1000747(2009).
RN [11]
RP INTERACTION WITH BMPR2; NOG; BMPR1A AND BMPR1B, FUNCTION, VARIANT BDA2
RP PRO-441, VARIANT SYNS2 ASN-475, CHARACTERIZATION OF VARIANT SYNS2 ASN-475,
RP AND CHARACTERIZATION OF VARIANT BDA2 PRO-441.
RX PubMed=21976273; DOI=10.1002/jbmr.532;
RA Schwaerzer G.K., Hiepen C., Schrewe H., Nickel J., Ploeger F., Sebald W.,
RA Mueller T., Knaus P.;
RT "New insights into the molecular mechanism of multiple synostoses syndrome
RT (SYNS): mutation within the GDF5 knuckle epitope causes noggin-
RT resistance.";
RL J. Bone Miner. Res. 27:429-442(2012).
RN [12]
RP INTERACTION WITH NOG; BMPR1B AND BMPR1A, FUNCTION, VARIANT SYNS2 ARG-414,
RP CHARACTERIZATION OF VARIANT SYNS2 ARG-414, VARIANT BDA1C ARG-414, AND
RP CHARACTERIZATION OF VARIANTS BDA1C CYS-399 AND ARG-414.
RX PubMed=24098149; DOI=10.1371/journal.pgen.1003846;
RA Degenkolbe E., Konig J., Zimmer J., Walther M., Reissner C., Nickel J.,
RA Ploger F., Raspopovic J., Sharpe J., Dathe K., Hecht J.T., Mundlos S.,
RA Doelken S.C., Seemann P.;
RT "A GDF5 point mutation strikes twice--causing BDA1 and SYNS2.";
RL PLoS Genet. 9:E1003846-E1003846(2013).
RN [13]
RP FUNCTION, VARIANTS BDC PRO-201 AND PRO-263, AND CHARACTERIZATION OF
RP VARIANTS BDC PRO-201 AND PRO-263.
RX PubMed=25092592; DOI=10.1016/j.jmb.2014.07.029;
RA Stange K., Thieme T., Hertel K., Kuhfahl S., Janecke A.R., Piza-Katzer H.,
RA Penttinen M., Hietala M., Dathe K., Mundlos S., Schwarz E., Seemann P.;
RT "Molecular analysis of two novel missense mutations in the GDF5 proregion
RT that reduce protein activity and are associated with brachydactyly type
RT C.";
RL J. Mol. Biol. 426:3221-3231(2014).
RN [14]
RP MUTAGENESIS OF TYR-490.
RX PubMed=26643732; DOI=10.1002/jbmr.2761;
RA Wang J., Yu T., Wang Z., Ohte S., Yao R.E., Zheng Z., Geng J., Cai H.,
RA Ge Y., Li Y., Xu Y., Zhang Q., Gusella J.F., Fu Q., Pregizer S., Rosen V.,
RA Shen Y.;
RT "A New Subtype of Multiple-Synostoses Syndrome is Caused by a Mutation in
RT GDF6 that Decreases its Sensitivity to Noggin and Enhances its Potency as a
RT BMP Signal.";
RL J. Bone Miner. Res. 31:882-889(2016).
RN [15]
RP INVOLVEMENT IN BDC.
RX PubMed=22828468; DOI=10.1016/j.ejmg.2012.07.004;
RA Gutierrez-Amavizca B.E., Brambila-Tapia A.J., Juarez-Vazquez C.I.,
RA Holder-Espinasse M., Manouvrier-Hanu S., Escande F., Barros-Nunez P.;
RT "A novel mutation in CDMP1 causes brachydactyly type C with 'angel-shaped
RT phalanx'. A genotype-phenotype correlation in the mutational spectrum.";
RL Eur. J. Med. Genet. 55:611-614(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 387-501 IN COMPLEX WITH MOUSE
RP BMPR1B, FUNCTION, AND DISULFIDE BONDS.
RX PubMed=19229295; DOI=10.1038/emboj.2009.37;
RA Kotzsch A., Nickel J., Seher A., Sebald W., Muller T.D.;
RT "Crystal structure analysis reveals a spring-loaded latch as molecular
RT mechanism for GDF-5-type I receptor specificity.";
RL EMBO J. 28:937-947(2009).
RN [17]
RP VARIANT AMD2A TYR-400.
RX PubMed=9288098; DOI=10.1038/ng0997-58;
RA Thomas J.T., Kilpatrick M.W., Lin K., Erlacher L., Lembessis P., Costa T.,
RA Tsipouras P., Luyten F.P.;
RT "Disruption of human limb morphogenesis by a dominant negative mutation in
RT CDMP1.";
RL Nat. Genet. 17:58-64(1997).
RN [18]
RP VARIANT SYNS2 ASN-475.
RA Akarsu A.N., Rezaie T., Demirtas M., Farhud D.D., Sarfarazi M.;
RT "Multiple synostosis type 2 (SYNS2) maps to 20q11.2 and caused by a
RT missense mutation in the growth/differentiation factor 5 (GDF5).";
RL Am. J. Hum. Genet. 65:A281-A281(1999).
RN [19]
RP VARIANT AMD2B PRO-441.
RX PubMed=12121354; DOI=10.1034/j.1399-0004.2002.610610.x;
RA Faiyaz-Ul-Haque M., Ahmad W., Zaidi S.H.E., Haque S., Teebi A.S., Ahmad M.,
RA Cohn D.H., Tsui L.-C.;
RT "Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in
RT a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan
RT syndrome).";
RL Clin. Genet. 61:454-458(2002).
RN [20]
RP VARIANT BDC VAL-173.
RX PubMed=14735582; DOI=10.1002/ajmg.a.20349;
RA Schwabe G.C., Tuerkmen S., Leschik G., Palanduz S., Stoever B.,
RA Goecke T.O., Mundlos S.;
RT "Brachydactyly type C caused by a homozygous missense mutation in the
RT prodomain of CDMP1.";
RL Am. J. Med. Genet. A 124:356-363(2004).
RN [21]
RP VARIANTS AMD2B LEU-437 DEL; THR-439 AND LEU-440.
RX PubMed=16222676; DOI=10.1002/ajmg.a.30969;
RA Szczaluba K., Hilbert K., Obersztyn E., Zabel B., Mazurczak T.,
RA Kozlowski K.;
RT "Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in
RT CDMP1 gene.";
RL Am. J. Med. Genet. A 138:379-383(2005).
RN [22]
RP VARIANT SYM1B LEU-438, VARIANT BDA2 PRO-441, CHARACTERIZATION OF VARIANT
RP SYM1B LEU-438, AND CHARACTERIZATION OF VARIANT BDA2 PRO-441.
RX PubMed=16127465; DOI=10.1172/jci25118;
RA Seemann P., Schwappacher R., Kjaer K.W., Krakow D., Lehmann K., Dawson K.,
RA Stricker S., Pohl J., Ploeger F., Staub E., Nickel J., Sebald W., Knaus P.,
RA Mundlos S.;
RT "Activating and deactivating mutations in the receptor interaction site of
RT GDF5 cause symphalangism or brachydactyly type A2.";
RL J. Clin. Invest. 115:2373-2381(2005).
RN [23]
RP VARIANT SYNS2 LEU-438.
RX PubMed=16532400; DOI=10.1086/503204;
RA Dawson K., Seeman P., Sebald E., King L., Edwards M., Williams J. III,
RA Mundlos S., Krakow D.;
RT "GDF5 is a second locus for multiple-synostosis syndrome.";
RL Am. J. Hum. Genet. 78:708-712(2006).
RN [24]
RP VARIANT SYM1B LYS-491.
RX PubMed=16892395; DOI=10.1002/ajmg.a.31372;
RA Wang X., Xiao F., Yang Q., Liang B., Tang Z., Jiang L., Zhu Q., Chang W.,
RA Jiang J., Jiang C., Ren X., Liu J.-Y., Wang Q.K., Liu M.;
RT "A novel mutation in GDF5 causes autosomal dominant symphalangism in two
RT Chinese families.";
RL Am. J. Med. Genet. A 140:1846-1853(2006).
RN [25]
RP INVOLVEMENT IN OS5.
RX PubMed=17384641; DOI=10.1038/2005;
RA Miyamoto Y., Mabuchi A., Shi D., Kubo T., Takatori Y., Saito S.,
RA Fujioka M., Sudo A., Uchida A., Yamamoto S., Ozaki K., Takigawa M.,
RA Tanaka T., Nakamura Y., Jiang Q., Ikegawa S.;
RT "A functional polymorphism in the 5' UTR of GDF5 is associated with
RT susceptibility to osteoarthritis.";
RL Nat. Genet. 39:529-533(2007).
RN [26]
RP VARIANTS AMD2B GLN-378 AND THR-436.
RX PubMed=18629880; DOI=10.1002/ajmg.a.32435;
RA Douzgou S., Lehmann K., Mingarelli R., Mundlos S., Dallapiccola B.;
RT "Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia.";
RL Am. J. Med. Genet. A 146:2116-2121(2008).
RN [27]
RP VARIANT BDA2 GLN-380, AND CHARACTERIZATION OF VARIANT BDA2 GLN-380.
RX PubMed=18203755; DOI=10.1093/hmg/ddn012;
RA Ploeger F., Seemann P., Schmidt-von Kegler M., Lehmann K., Seidel J.,
RA Kjaer K.W., Pohl J., Mundlos S.;
RT "Brachydactyly type A2 associated with a defect in proGDF5 processing.";
RL Hum. Mol. Genet. 17:1222-1233(2008).
RN [28]
RP VARIANT SYM1B ARG-373, AND CHARACTERIZATION OF VARIANT SYM1B ARG-373.
RX PubMed=18283415; DOI=10.1007/s10038-008-0253-7;
RA Yang W., Cao L., Liu W., Jiang L., Sun M., Zhang D., Wang S., Lo W.H.,
RA Luo Y., Zhang X.;
RT "Novel point mutations in GDF5 associated with two distinct limb
RT malformations in Chinese: brachydactyly type C and proximal
RT symphalangism.";
RL J. Hum. Genet. 53:368-374(2008).
RN [29]
RP VARIANT BDA1C CYS-399, AND CHARACTERIZATION OF VARIANT BDA1C CYS-399.
RX PubMed=20683927; DOI=10.1002/humu.21338;
RA Byrnes A.M., Racacho L., Nikkel S.M., Xiao F., MacDonald H.,
RA Underhill T.M., Bulman D.E.;
RT "Mutations in GDF5 presenting as semidominant brachydactyly A1.";
RL Hum. Mutat. 31:1155-1162(2010).
RN [30]
RP VARIANTS BDC ASN-203 AND MET-486.
RX PubMed=25820810; DOI=10.1002/ajmg.a.37040;
RA Al-Qattan M.M., Al-Motairi M.I., Al Balwi M.A.;
RT "Two novel homozygous missense mutations in the GDF5 gene cause
RT brachydactyly type C.";
RL Am. J. Med. Genet. A 167:1621-1626(2015).
CC -!- FUNCTION: Growth factor involved in bone and cartilage formation.
CC During cartilage development regulates differentiation of chondrogenic
CC tissue through two pathways. Firstly, positively regulates
CC differentiation of chondrogenic tissue through its binding of high
CC affinity with BMPR1B and of less affinity with BMPR1A, leading to
CC induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD
CC protein signaling transduction (PubMed:24098149, PubMed:21976273,
CC PubMed:15530414, PubMed:25092592). Secondly, negatively regulates
CC chondrogenic differentiation through its interaction with NOG
CC (PubMed:21976273). Required to prevent excessive muscle loss upon
CC denervation. This function requires SMAD4 and is mediated by
CC phosphorylated SMAD1/5/8 (By similarity). Binds bacterial
CC lipopolysaccharide (LPS) and mediates LPS-induced inflammatory
CC response, including TNF secretion by monocytes (PubMed:11276205).
CC {ECO:0000250|UniProtKB:P43027, ECO:0000269|PubMed:11276205,
CC ECO:0000269|PubMed:15530414, ECO:0000269|PubMed:19229295,
CC ECO:0000269|PubMed:19956691, ECO:0000269|PubMed:21976273,
CC ECO:0000269|PubMed:24098149, ECO:0000269|PubMed:25092592}.
CC -!- SUBUNIT: Homodimer; disulfide-linked (By similarity). Interacts with
CC serine proteases, HTRA1 and HTRA3 (By similarity). Following LPS
CC binding, may form a complex with CXCR4, HSP90AA1 and HSPA8. Interacts
CC with high affinity with NOG; inhibits chondrogenesis. Interacts with
CC high affinity with BMPR1B and lower affinity with BMPR1A; positively
CC regulates chondrocyte differentiation and induces SMAD dependent
CC signaling. Interacts with FBN1 (via N-terminal domain) and FBN2
CC (PubMed:18339631). {ECO:0000250|UniProtKB:P43027,
CC ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:18339631,
CC ECO:0000269|PubMed:19229295, ECO:0000269|PubMed:19956691,
CC ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:24098149}.
CC -!- INTERACTION:
CC P43026; P36894: BMPR1A; NbExp=4; IntAct=EBI-8571476, EBI-1029237;
CC P43026; O00238: BMPR1B; NbExp=7; IntAct=EBI-8571476, EBI-7527193;
CC P43026; Q13873: BMPR2; NbExp=4; IntAct=EBI-8571476, EBI-527196;
CC P43026; P43026: GDF5; NbExp=2; IntAct=EBI-8571476, EBI-8571476;
CC PRO_0000033913; P98066: TNFAIP6; NbExp=3; IntAct=EBI-11710512, EBI-11700693;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11276205}. Cell
CC membrane {ECO:0000269|PubMed:11276205}.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in long bones during
CC embryonic development. Expressed in monocytes (at protein level).
CC {ECO:0000269|PubMed:11276205}.
CC -!- DISEASE: Acromesomelic dysplasia 2A (AMD2A) [MIM:200700]: A form of
CC acromesomelic dysplasia, a skeletal disorder characterized by short
CC stature, very short limbs and hand/foot malformations. The severity of
CC limb abnormalities increases from proximal to distal with profoundly
CC affected hands and feet showing brachydactyly and/or rudimentary
CC fingers (knob-like fingers). AMD2A is an autosomal recessive form
CC characterized by normal axial skeletons and missing or fused skeletal
CC elements within the hands and feet. {ECO:0000269|PubMed:9288098}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Acromesomelic dysplasia 2C (AMD2C) [MIM:201250]: A form of
CC acromesomelic dysplasia, a skeletal disorder characterized by short
CC stature, very short limbs and hand/foot malformations. The severity of
CC limb abnormalities increases from proximal to distal with profoundly
CC affected hands and feet showing brachydactyly and/or rudimentary
CC fingers (knob-like fingers). AMD2C is an autosomal recessive form
CC characterized by skeletal abnormalities restricted to the limbs. The
CC craniofacial skeleton and axial skeletal structures are normal.
CC {ECO:0000269|PubMed:8589725}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Brachydactyly C (BDC) [MIM:113100]: A form of brachydactyly.
CC Brachydactyly defines a group of inherited malformations characterized
CC by shortening of the digits due to abnormal development of the
CC phalanges and/or the metacarpals. Brachydactyly type C is characterized
CC by deformity of the middle and proximal phalanges of the second and
CC third fingers, sometimes with hypersegmentation of the proximal
CC phalanx. The ring finger may be essentially normal and project beyond
CC the others. {ECO:0000269|PubMed:14735582, ECO:0000269|PubMed:22828468,
CC ECO:0000269|PubMed:25092592, ECO:0000269|PubMed:25820810}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Some BDC patients with GDF5 mutations also manifest clinical
CC features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED),
CC an autosomal dominant skeletal abnormality characterized by a typical
CC angel-shaped phalanx, brachydactyly, specific radiological findings,
CC abnormal dentition, hip dysplasia, and delayed bone age. This suggests
CC that BDC and ASPED are part of the same clinical spectrum
CC (PubMed:22828468). {ECO:0000269|PubMed:22828468}.
CC -!- DISEASE: Acromesomelic dysplasia 2B (AMD2B) [MIM:228900]: A form of
CC acromesomelic dysplasia, a skeletal disorder characterized by short
CC stature, very short limbs and hand/foot malformations. The severity of
CC limb abnormalities increases from proximal to distal with profoundly
CC affected hands and feet showing brachydactyly and/or rudimentary
CC fingers (knob-like fingers). AMD2B is an autosomal recessive form
CC characterized by acromesomelic limb shortening with severe reduction or
CC absence of the fibula, and severe hand and feet abnormalities including
CC complex brachydactyly. {ECO:0000269|PubMed:12121354,
CC ECO:0000269|PubMed:16222676, ECO:0000269|PubMed:18629880}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Symphalangism, proximal 1B (SYM1B) [MIM:615298]: A disease
CC characterized by the hereditary absence of the proximal interphalangeal
CC joints. Distal interphalangeal joints are less frequently involved and
CC metacarpophalangeal joints are rarely affected whereas carpal bone
CC malformation and fusion are common. In the lower extremities, tarsal
CC bone coalition is common. Conductive hearing loss is seen and is due to
CC fusion of the stapes to the petrous part of the temporal bone.
CC {ECO:0000269|PubMed:16127465, ECO:0000269|PubMed:16892395,
CC ECO:0000269|PubMed:18283415}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Multiple synostoses syndrome 2 (SYNS2) [MIM:610017]: A bone
CC disease characterized by multiple progressive joint fusions that
CC commonly involve proximal interphalangeal, tarsal-carpal, humeroradial
CC and cervical spine joints. Additional features can include progressive
CC conductive deafness and facial dysmorphism.
CC {ECO:0000269|PubMed:16532400, ECO:0000269|PubMed:19956691,
CC ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:24098149,
CC ECO:0000269|Ref.18}. Note=The disease is caused by variants affecting
CC the gene represented in this entry.
CC -!- DISEASE: Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly.
CC Brachydactyly defines a group of inherited malformations characterized
CC by shortening of the digits due to abnormal development of the
CC phalanges and/or the metacarpals. In brachydactyly type A2 shortening
CC of the middle phalanges is confined to the index finger and the second
CC toe, all other digits being more or less normal. Because of a rhomboid
CC or triangular shape of the affected middle phalanx, the end of the
CC second finger usually deviates radially. {ECO:0000269|PubMed:16127465,
CC ECO:0000269|PubMed:18203755, ECO:0000269|PubMed:21976273}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Osteoarthritis 5 (OS5) [MIM:612400]: A degenerative disease of
CC the joints characterized by degradation of the hyaline articular
CC cartilage and remodeling of the subchondral bone with sclerosis.
CC Clinical symptoms include pain and joint stiffness often leading to
CC significant disability and joint replacement.
CC {ECO:0000269|PubMed:17384641}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Brachydactyly A1, C (BDA1C) [MIM:615072]: A form of
CC brachydactyly type A1. Brachydactyly defines a group of inherited
CC malformations characterized by shortening of the digits due to abnormal
CC development of the phalanges and/or the metacarpals. Brachydactyly type
CC A1 is characterized by middle phalanges of all the digits rudimentary
CC or fused with the terminal phalanges. The proximal phalanges of the
CC thumbs and big toes are short. BDA1C inheritance can be autosomal
CC dominant or autosomal recessive. Autosomal dominant BDA1C has a milder
CC phenotype. {ECO:0000269|PubMed:20683927, ECO:0000269|PubMed:24098149}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB89416.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=GDF5 entry;
CC URL="https://en.wikipedia.org/wiki/GDF5";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X80915; CAA56874.1; -; Genomic_DNA.
DR EMBL; U13660; AAA57007.1; -; mRNA.
DR EMBL; AL121586; CAB89416.1; ALT_SEQ; Genomic_DNA.
DR EMBL; FO393401.1; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471077; EAW76208.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW76209.1; -; Genomic_DNA.
DR EMBL; BC032495; AAH32495.1; -; mRNA.
DR CCDS; CCDS13254.1; -.
DR PIR; A55452; A55452.
DR PIR; JC2347; JC2347.
DR RefSeq; NP_000548.2; NM_000557.4.
DR RefSeq; NP_001306067.1; NM_001319138.1.
DR RefSeq; XP_011527377.1; XM_011529075.2.
DR PDB; 1WAQ; X-ray; 2.28 A; A=387-501.
DR PDB; 2BHK; X-ray; 2.40 A; A=382-501.
DR PDB; 3EVS; X-ray; 2.10 A; B=387-501.
DR PDB; 3QB4; X-ray; 2.28 A; A/C=387-501.
DR PDB; 5HK5; X-ray; 2.90 A; A/B/C/D=382-501.
DR PDB; 6Z3G; X-ray; 2.78 A; A=387-501.
DR PDB; 6Z3H; X-ray; 3.16 A; A=387-501.
DR PDB; 6Z3J; X-ray; 1.65 A; A/B=387-501.
DR PDB; 6Z3L; X-ray; 2.51 A; A=387-501.
DR PDB; 6Z3M; X-ray; 5.50 A; A/B/G/H/M/N=387-501.
DR PDBsum; 1WAQ; -.
DR PDBsum; 2BHK; -.
DR PDBsum; 3EVS; -.
DR PDBsum; 3QB4; -.
DR PDBsum; 5HK5; -.
DR PDBsum; 6Z3G; -.
DR PDBsum; 6Z3H; -.
DR PDBsum; 6Z3J; -.
DR PDBsum; 6Z3L; -.
DR PDBsum; 6Z3M; -.
DR AlphaFoldDB; P43026; -.
DR SMR; P43026; -.
DR BioGRID; 113839; 33.
DR DIP; DIP-5823N; -.
DR IntAct; P43026; 26.
DR MINT; P43026; -.
DR STRING; 9606.ENSP00000363492; -.
DR GlyGen; P43026; 1 site.
DR iPTMnet; P43026; -.
DR PhosphoSitePlus; P43026; -.
DR SwissPalm; P43026; -.
DR BioMuta; GDF5; -.
DR DMDM; 20141384; -.
DR EPD; P43026; -.
DR PaxDb; P43026; -.
DR PeptideAtlas; P43026; -.
DR PRIDE; P43026; -.
DR ProteomicsDB; 55574; -.
DR Antibodypedia; 2854; 410 antibodies from 31 providers.
DR DNASU; 8200; -.
DR Ensembl; ENST00000374369.8; ENSP00000363489.3; ENSG00000125965.9.
DR Ensembl; ENST00000374372.1; ENSP00000363492.1; ENSG00000125965.9.
DR GeneID; 8200; -.
DR KEGG; hsa:8200; -.
DR MANE-Select; ENST00000374369.8; ENSP00000363489.3; NM_000557.5; NP_000548.2.
DR UCSC; uc002xck.2; human.
DR CTD; 8200; -.
DR DisGeNET; 8200; -.
DR GeneCards; GDF5; -.
DR HGNC; HGNC:4220; GDF5.
DR HPA; ENSG00000125965; Tissue enriched (salivary).
DR MalaCards; GDF5; -.
DR MIM; 112600; phenotype.
DR MIM; 113100; phenotype.
DR MIM; 200700; phenotype.
DR MIM; 201250; phenotype.
DR MIM; 228900; phenotype.
DR MIM; 601146; gene.
DR MIM; 610017; phenotype.
DR MIM; 612400; phenotype.
DR MIM; 615072; phenotype.
DR MIM; 615298; phenotype.
DR neXtProt; NX_P43026; -.
DR OpenTargets; ENSG00000125965; -.
DR Orphanet; 2098; Acromesomelic dysplasia, Grebe type.
DR Orphanet; 968; Acromesomelic dysplasia, Hunter-Thompson type.
DR Orphanet; 63442; Angel-shaped phalango-epiphyseal dysplasia.
DR Orphanet; 93388; Brachydactyly type A1.
DR Orphanet; 93396; Brachydactyly type A2.
DR Orphanet; 93384; Brachydactyly type C.
DR Orphanet; 2639; Fibular aplasia-complex brachydactyly syndrome.
DR Orphanet; 3237; Multiple synostoses syndrome.
DR Orphanet; 3250; Proximal symphalangism.
DR PharmGKB; PA28635; -.
DR VEuPathDB; HostDB:ENSG00000125965; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000160455; -.
DR HOGENOM; CLU_020515_0_0_1; -.
DR InParanoid; P43026; -.
DR OrthoDB; 749511at2759; -.
DR PhylomeDB; P43026; -.
DR TreeFam; TF316134; -.
DR PathwayCommons; P43026; -.
DR Reactome; R-HSA-2129379; Molecules associated with elastic fibres.
DR SignaLink; P43026; -.
DR SIGNOR; P43026; -.
DR BioGRID-ORCS; 8200; 15 hits in 1069 CRISPR screens.
DR EvolutionaryTrace; P43026; -.
DR GeneWiki; GDF5; -.
DR GenomeRNAi; 8200; -.
DR Pharos; P43026; Tbio.
DR PRO; PR:P43026; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; P43026; protein.
DR Bgee; ENSG00000125965; Expressed in parotid gland and 108 other tissues.
DR ExpressionAtlas; P43026; baseline and differential.
DR Genevisible; P43026; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0036122; F:BMP binding; IPI:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0060591; P:chondroblast differentiation; IDA:UniProtKB.
DR GO; GO:0002062; P:chondrocyte differentiation; IEA:Ensembl.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR GO; GO:0035136; P:forelimb morphogenesis; IEA:Ensembl.
DR GO; GO:0035137; P:hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:0097152; P:mesenchymal cell apoptotic process; IEA:Ensembl.
DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; IDA:UniProtKB.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0043932; P:ossification involved in bone remodeling; IEA:Ensembl.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IDA:UniProtKB.
DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; IDA:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0060390; P:regulation of SMAD protein signal transduction; IDA:UniProtKB.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:UniProtKB.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR001111; TGF-b_propeptide.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR017948; TGFb_CS.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Chondrogenesis;
KW Cleavage on pair of basic residues; Cytokine; Disease variant;
KW Disulfide bond; Dwarfism; Glycoprotein; Growth factor; Membrane;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..27
FT /evidence="ECO:0000255"
FT PROPEP 28..381
FT /evidence="ECO:0000255"
FT /id="PRO_0000033912"
FT CHAIN 382..501
FT /note="Growth/differentiation factor 5"
FT /id="PRO_0000033913"
FT REGION 29..169
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 246..265
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 189
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 400..466
FT /evidence="ECO:0000269|PubMed:19229295"
FT DISULFID 429..498
FT /evidence="ECO:0000269|PubMed:19229295"
FT DISULFID 433..500
FT /evidence="ECO:0000269|PubMed:19229295"
FT DISULFID 465
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT VARIANT 163
FT /note="R -> G (in dbSNP:rs34534075)"
FT /id="VAR_037977"
FT VARIANT 173
FT /note="M -> V (in BDC; dbSNP:rs28936397)"
FT /evidence="ECO:0000269|PubMed:14735582"
FT /id="VAR_037978"
FT VARIANT 201
FT /note="T -> P (in BDC; decrease of induction of SMAD
FT protein signal transduction with either BMPR1A or BMPR1B;
FT less induction of chondrgenesis; no phosphorylation of
FT SMAD1-SMAD5-SMAD8 protein complex; reduction of protein
FT level; abnormal proteolysis product)"
FT /evidence="ECO:0000269|PubMed:25092592"
FT /id="VAR_073139"
FT VARIANT 203
FT /note="T -> N (in BDC)"
FT /evidence="ECO:0000269|PubMed:25820810"
FT /id="VAR_074161"
FT VARIANT 263
FT /note="L -> P (in BDC; no induction of SMAD protein signal
FT transduction via BMPR1A; less induction of chondrgenesis;
FT no phosphorylation of SMAD1-SMAD5-SMAD8 protein complex;
FT reduction of protein level; abnormal proteolysis product)"
FT /evidence="ECO:0000269|PubMed:25092592"
FT /id="VAR_073140"
FT VARIANT 276
FT /note="A -> S (in dbSNP:rs224331)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7980526"
FT /id="VAR_026120"
FT VARIANT 373
FT /note="L -> R (in SYM1B; the mature GDF5 protein is
FT detected as the wild-type in the supernatant derived from
FT the mutant transfected cells; dbSNP:rs121909349)"
FT /evidence="ECO:0000269|PubMed:18283415"
FT /id="VAR_054909"
FT VARIANT 378
FT /note="R -> Q (in AMD2B; dbSNP:rs121909350)"
FT /evidence="ECO:0000269|PubMed:18629880"
FT /id="VAR_054910"
FT VARIANT 380
FT /note="R -> Q (in BDA2; reduces activity; impairs
FT processing; dbSNP:rs397514668)"
FT /evidence="ECO:0000269|PubMed:18203755"
FT /id="VAR_046743"
FT VARIANT 399
FT /note="R -> C (in BDA1C; less effective than wild-type in
FT stimulating chondrogenesis; impairs BMP signaling through
FT BMPR1A; dbSNP:rs397514519)"
FT /evidence="ECO:0000269|PubMed:20683927,
FT ECO:0000269|PubMed:24098149"
FT /id="VAR_064416"
FT VARIANT 400
FT /note="C -> Y (in AMD2A; dbSNP:rs74315387)"
FT /evidence="ECO:0000269|PubMed:9288098"
FT /id="VAR_017407"
FT VARIANT 414
FT /note="W -> R (in SYNS2 and BDA1C; reduced interaction with
FT NOG; reduces affinity to BMPR1A; impairs BMP signaling
FT through BMPR1A; impairs chondrogenesis)"
FT /evidence="ECO:0000269|PubMed:24098149"
FT /id="VAR_073141"
FT VARIANT 436
FT /note="P -> T (in AMD2B; dbSNP:rs121909351)"
FT /evidence="ECO:0000269|PubMed:18629880"
FT /id="VAR_054911"
FT VARIANT 437
FT /note="Missing (in AMD2B; located on the same allele as T-
FT 439 and L-440)"
FT /evidence="ECO:0000269|PubMed:16222676"
FT /id="VAR_037979"
FT VARIANT 438
FT /note="R -> L (in SYNS2 and SYM1B; increased biological
FT activity when compared to wild-type; normal binding to
FT BMPR1B ectodomain but increased binding to that of BMPR1A;
FT dbSNP:rs74315388)"
FT /evidence="ECO:0000269|PubMed:16127465,
FT ECO:0000269|PubMed:16532400"
FT /id="VAR_026545"
FT VARIANT 439
FT /note="S -> T (in AMD2B; located on the same allele as L-
FT 437 del and L-440)"
FT /evidence="ECO:0000269|PubMed:16222676"
FT /id="VAR_037980"
FT VARIANT 440
FT /note="H -> L (in AMD2B; located on the same allele as L-
FT 437 del and T-439)"
FT /evidence="ECO:0000269|PubMed:16222676"
FT /id="VAR_037981"
FT VARIANT 441
FT /note="L -> P (in AMD2B, SYNS2 and BDA2; the mutant is
FT almost inactive; loss of binding to BMPR1A and BMPR1B
FT ectodomains; no induction of SMAD1-SMAD5-SMAD8 protein
FT complex phosphorylation; impairs nuclear translocation of
FT phosphotylated SMAD1-SMAD5-SMAD8 protein complex; no
FT ability to induce SMAD protein signal transduction; binds
FT to NOG; dbSNP:rs28936683)"
FT /evidence="ECO:0000269|PubMed:12121354,
FT ECO:0000269|PubMed:16127465, ECO:0000269|PubMed:21976273"
FT /id="VAR_017408"
FT VARIANT 445
FT /note="N -> K (in SYNS2)"
FT /evidence="ECO:0000269|PubMed:19956691"
FT /id="VAR_073142"
FT VARIANT 445
FT /note="N -> T (in SYNS2; resistant to NOG inhibition; no
FT change in binding with MPR1A and BMPR1B; strong induction
FT of chondrogenesis)"
FT /evidence="ECO:0000269|PubMed:19956691"
FT /id="VAR_073143"
FT VARIANT 475
FT /note="S -> N (in SYNS2; reduction in binding affinity with
FT BMPR2; no change in binding affinity with BMPR1A; no change
FT in binding affinity with BMPR1B; decreases induction of
FT SMAD1-SMAD5-SMAD8 protein complex phosphorylation; delay of
FT phosphotylated SMAD1-SMAD5-SMAD8 protein complex nuclear
FT translocation; strong reduction of SMAD protein signal
FT transduction; reduction of chondrocyte differentiation;
FT strong improvement of chondrogenesis; decrease of NOG
FT binding; resistant to NOG inhibition; no chondrogenesis
FT inhibition; dbSNP:rs121909347)"
FT /evidence="ECO:0000269|PubMed:21976273, ECO:0000269|Ref.18"
FT /id="VAR_037982"
FT VARIANT 486
FT /note="V -> M (in BDC)"
FT /evidence="ECO:0000269|PubMed:25820810"
FT /id="VAR_074162"
FT VARIANT 491
FT /note="E -> K (in SYM1B; dbSNP:rs74315389)"
FT /evidence="ECO:0000269|PubMed:16892395"
FT /id="VAR_037983"
FT MUTAGEN 490
FT /note="Y->N: Resitant to NOG inhibition."
FT /evidence="ECO:0000269|PubMed:26643732"
FT CONFLICT 38
FT /note="T -> S (in Ref. 2; AAA57007)"
FT /evidence="ECO:0000305"
FT CONFLICT 254..258
FT /note="APGGG -> VPRSR (in Ref. 2; AAA57007)"
FT /evidence="ECO:0000305"
FT CONFLICT 321
FT /note="A -> T (in Ref. 2; AAA57007)"
FT /evidence="ECO:0000305"
FT CONFLICT 384
FT /note="L -> S (in Ref. 2; AAA57007)"
FT /evidence="ECO:0000305"
FT STRAND 399..403
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 406..408
FT /evidence="ECO:0007829|PDB:6Z3J"
FT TURN 409..413
FT /evidence="ECO:0007829|PDB:6Z3J"
FT HELIX 414..416
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 418..420
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 422..425
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 428..432
FT /evidence="ECO:0007829|PDB:6Z3J"
FT HELIX 439..441
FT /evidence="ECO:0007829|PDB:6Z3J"
FT HELIX 445..456
FT /evidence="ECO:0007829|PDB:6Z3J"
FT TURN 458..460
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 466..479
FT /evidence="ECO:0007829|PDB:6Z3J"
FT STRAND 481..483
FT /evidence="ECO:0007829|PDB:3QB4"
FT STRAND 485..500
FT /evidence="ECO:0007829|PDB:6Z3J"
SQ SEQUENCE 501 AA; 55395 MW; FEBACCFBD7597C37 CRC64;
MRLPKLLTFL LWYLAWLDLE FICTVLGAPD LGQRPQGTRP GLAKAEAKER PPLARNVFRP
GGHSYGGGAT NANARAKGGT GQTGGLTQPK KDEPKKLPPR PGGPEPKPGH PPQTRQATAR
TVTPKGQLPG GKAPPKAGSV PSSFLLKKAR EPGPPREPKE PFRPPPITPH EYMLSLYRTL
SDADRKGGNS SVKLEAGLAN TITSFIDKGQ DDRGPVVRKQ RYVFDISALE KDGLLGAELR
ILRKKPSDTA KPAAPGGGRA AQLKLSSCPS GRQPAALLDV RSVPGLDGSG WEVFDIWKLF
RNFKNSAQLC LELEAWERGR AVDLRGLGFD RAARQVHEKA LFLVFGRTKK RDLFFNEIKA
RSGQDDKTVY EYLFSQRRKR RAPLATRQGK RPSKNLKARC SRKALHVNFK DMGWDDWIIA
PLEYEAFHCE GLCEFPLRSH LEPTNHAVIQ TLMNSMDPES TPPTCCVPTR LSPISILFID
SANNVVYKQY EDMVVESCGC R
