Sonic hedgehog protein precursor - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot Q15465 (SHH_HUMAN)

Last modified November 25, 2008. Version 105. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Sonic hedgehog protein
      Short name=SHH
Alternative name(s):
    HHG-1
Cleaved into the following 2 chains:
    1- Recommended name:
            Sonic hedgehog protein N-product
    2- Recommended name:
            Sonic hedgehog protein C-product

Gene names

Name:

SHH

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	462 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction By similarity.
Subunit structure	Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. N-product is active as a multimer By similarity.
Subcellular location	Sonic hedgehog protein C-product: Secreted › extracellular spaceBy similarity. Note= The C-terminal peptide diffuses from the cell By similarity. Sonic hedgehog protein N-product: Cell membrane; Lipid-anchorBy similarity. Note= The N-product either remains associated with lipid rafts at the cell surface, or forms freely diffusible active multimers with its hydrophobic lipid-modified N- and C-termini buried inside By similarity.
Tissue specificity	Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues.
Post-translational modification	The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity. Cholesterylation is required for N-product targeting to lipid rafts and multimerization By similarity. N-palmitoylation of Cys-24 by HHAT is required for N-product multimerization and full activity By similarity.
Involvement in disease	Defects in SHH are the cause of isolated microphthalmia with coloboma type 5 (MCOPCB5) [MIM:611638]. Microphtalmia consists of a development defect causing moderate or severe reduction in size of the eye. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Severe colobomatous malformations may cause as much as 10% of the childhood blindness. The clinical presentation of ocular coloboma is variable. Some individuals may present with minimal defects in the anterior iris leaf without other ocular defects. More complex malformations create a combination of iris, uveoretinal and/or optic nerve defects without or with microphthalmia or even anophthalmia. Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:142945]. Holoprosencephaly (HPE) [MIM:236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear exemples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected. Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor. Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.
Sequence similarities	Belongs to the hedgehog family.
Mass spectrometry	Molecular weight is 19.560 Da from positions 24 - 197. Determined by ESI. Soluble N-product, purified from insect cells. Ref.5 Molecular weight is 20.167 Da from positions 24 - 197. Determined by ESI. Membrane-bound N-product, purified from insect cells. Ref.5

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Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Disease	Disease mutation Holoprosencephaly
Domain	Signal
Molecular function	Developmental protein Hydrolase Protease
PTM	Autocatalytic cleavage Glycoprotein Lipoprotein Palmitate
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	androgen metabolic process Inferred from sequence or structural similarity. Source: UniProtKB axon guidance Inferred from sequence or structural similarity. Source: UniProtKB cell fate specification Inferred from sequence or structural similarity. Source: UniProtKB embryonic digit morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB heart development Inferred from sequence or structural similarity. Source: UniProtKB intein-mediated protein splicing Inferred from electronic annotation. Source: InterPro lung development Inferred from sequence or structural similarity. Source: UniProtKB male genitalia development Inferred from sequence or structural similarity. Source: UniProtKB midbrain development Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell migration Inferred from sequence or structural similarity. Source: UniProtKB neural crest cell migration Inferred from sequence or structural similarity. Source: UniProtKB neuron fate commitment Inferred from sequence or structural similarity. Source: UniProtKB patterning of blood vessels Inferred from sequence or structural similarity. Source: UniProtKB prostate gland development Inferred from sequence or structural similarity. Source: UniProtKB salivary gland morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB ureteric bud branching Inferred from sequence or structural similarity. Source: UniProtKB vasculogenesis Inferred from sequence or structural similarity. Source: UniProtKB ventral midline development Ref.9 Traceable author statement. Source: ProtInc
Cellular component	cell surface Inferred from sequence or structural similarity. Source: UniProtKB extracellular space Inferred from sequence or structural similarity. Source: UniProtKB membrane raft Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	laminin-1 binding Inferred from sequence or structural similarity. Source: UniProtKB peptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

Chain

24 – 462

439

Sonic hedgehog protein

PRO_0000013208

Chain

24 – 197

174

Sonic hedgehog protein N-product

PRO_0000013209

Chain

198 – 462

265

Sonic hedgehog protein C-product

PRO_0000013210

Regions

Compositional bias

407 – 411

Poly-Gly

Sites

Site

197 – 198

Cleavage; by autolysis By similarity

Site

243

Involved in cholesterol transfer By similarity

Site

267

Involved in auto-cleavage By similarity

Site

270

Essential for auto-cleavage By similarity

Amino acid modifications

Lipidation

N-palmitoyl cysteine

Lipidation

197

Cholesterol glycine ester By similarity

Glycosylation

278

N-linked (GlcNAc...)

Natural variations

Natural variant

R → T in HPE3.

VAR_023804

Natural variant

G → A in HPE3.

VAR_039888

Natural variant

G → R in HPE3. dbSNP rs28936675.

VAR_003619

Natural variant

D → V in HPE3; familial.

VAR_009163

Natural variant

100

Q → H in HPE3; sporadic.

VAR_009164

Natural variant

106 – 107

Missing in HPE3.

VAR_023805

Natural variant

110

A → D in HPE3.

VAR_023806

Natural variant

111

I → F in SMMCI.

VAR_017883

Natural variant

111

I → N in HPE3.

VAR_039889

Natural variant

115

N → K in HPE3; familial.

VAR_009165

Natural variant

117

W → G in HPE3.

VAR_003620

Natural variant

117

W → R in HPE3.

VAR_003621

Natural variant

140

H → P in HPE3.

VAR_039890

Natural variant

140

H → Q in HPE3.

VAR_039891

Natural variant

150

T → R in HPE3.

VAR_023807

Natural variant

176 – 178

Missing in HPE3.

VAR_023808

Natural variant

183

C → F in HPE3.

VAR_039892

Natural variant

188

E → Q in HPE3; familial.

VAR_009166

Natural variant

222

D → N in HPE3; familial.

VAR_009167

Natural variant

224

V → E in HPE3.

VAR_009168

Natural variant

226

A → T in HPE3; familial.

VAR_009169

Natural variant

236

S → R in HPE3; familial.

VAR_009170

Natural variant

263 – 269

Missing in HPE3; sporadic.

VAR_009171

Natural variant

267

T → I in HPE3.

VAR_039893

Natural variant

271

L → P in HPE3.

VAR_023809

Natural variant

290

G → D in HPE3; sporadic.

VAR_009172

Natural variant

332

V → A in HPE3.

VAR_023810

Natural variant

347

P → Q in HPE3.

VAR_023811

Natural variant

354

I → T in HPE3.

VAR_023812

Natural variant

373

A → T in HPE3.

VAR_039894

Natural variant

378 – 380

Missing in HPE3; familial.

VAR_009173

Natural variant

381

R → P in HPE3.

VAR_023813

Natural variant

383

A → T in HPE3; sporadic.

VAR_009174

Natural variant

401 – 408

Missing in ocular coloboma.

VAR_017884

Natural variant

404 – 408

Missing in HPE3; familial.

VAR_009175

Natural variant

424

P → A in HPE3; familial.

VAR_009176

Natural variant

436

S → L in HPE3; sporadic.

VAR_009177

Experimental info

Mutagenesis

C → S: Abolishes palmitoylation

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Sequences

Sequence

Length

Mass (Da)

Tools

Q15465-1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: DD687AFA582A4749
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FASTA

462

49,607

        10         20         30         40         50         60 
MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN VAEKTLGASG 

        70         80         90        100        110        120 
RYEGKISRNS ERFKELTPNY NPDIIFKDEE NTGADRLMTQ RCKDKLNALA ISVMNQWPGV 

       130        140        150        160        170        180 
KLRVTEGWDE DGHHSEESLH YEGRAVDITT SDRDRSKYGM LARLAVEAGF DWVYYESKAH 

       190        200        210        220        230        240 
IHCSVKAENS VAAKSGGCFP GSATVHLEQG GTKLVKDLSP GDRVLAADDQ GRLLYSDFLT 

       250        260        270        280        290        300 
FLDRDDGAKK VFYVIETREP RERLLLTAAH LLFVAPHNDS ATGEPEASSG SGPPSGGALG 

       310        320        330        340        350        360 
PRALFASRVR PGQRVYVVAE RDGDRRLLPA AVHSVTLSEE AAGAYAPLTA QGTILINRVL 

       370        380        390        400        410        420 
ASCYAVIEEH SWAHRAFAPF RLAHALLAAL APARTDRGGD SGGGDRGGGG GRVALTAPGA 

       430        440        450        460 
ADAPGAGATA GIHWYSQLLY QIGTWLLDSE ALHPLGMAVK SS

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References

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[1]	"Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog." Marigo V., Roberts D.J., Lee S.M.K., Tsukurov O., Levi T., Gastier J.M., Epstein D.J., Gilbert D.J., Copeland N.G., Seidman C.E., Jenkins N.A., Seidman J.G., McMahon A.P., Tabin C. Genomics 28:44-51(1995) [PubMed: 7590746] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal lung.
[2]	"Expression of Sonic hedgehog and its receptor Patched/Smoothened in human cancer cell lines and embryonic organs." Tate G., Kishimoto K., Mitsuya T. J. Biochem. Mol. Biol. Biophys. 4:27-34(2000) Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Daniels M.R., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Identification of a palmitic acid-modified form of human Sonic hedgehog." Pepinsky R.B., Zeng C., Wen D., Rayhorn P., Baker D.P., Williams K.P., Bixler S.A., Ambrose C.M., Garber E.A., Miatkowski K., Taylor F.R., Wang E.A., Galdes A. J. Biol. Chem. 273:14037-14045(1998) [PubMed: 9593755] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-32, PALMITOYLATION AT CYS-24, CHOLESTERYLATION, MUTAGENESIS OF CYS-24, MASS SPECTROMETRY.
[6]	"Products, genetic linkage and limb patterning activity of a murine hedgehog gene." Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R., Seldin M.F., Fallon J.F., Beachy P.A. Development 120:3339-3353(1994) [PubMed: 7720571] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 119-167.
[7]	"A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly." Lettice L.A., Heaney S.J.H., Purdie L.A., Li L., de Beer P., Oostra B.A., Goode D., Elgar G., Hill R.E., de Graaff E. Hum. Mol. Genet. 12:1725-1735(2003) [PubMed: 12837695] [Abstract] Cited for: INVOLVEMENT IN TPTPS.
[8]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278, MASS SPECTROMETRY. Tissue: Plasma.
[9]	"Mutations in the human Sonic hedgehog gene cause holoprosencephaly." Roessler E., Belloni E., Gaudenz K., Jay P., Berta P., Scherer S.W., Tsui L.-C., Muenke M. Nat. Genet. 14:357-360(1996) [PubMed: 8896572] [Abstract] Cited for: VARIANTS HPE3 ARG-31; GLY-117 AND ARG-117.
[10]	"Mutations in the C-terminal domain of Sonic hedgehog cause holoprosencephaly." Roessler E., Belloni E., Gaudenz K., Vargas F., Scherer S.W., Tsui L.-C., Muenke M. Hum. Mol. Genet. 6:1847-1853(1997) [PubMed: 9302262] [Abstract] Cited for: VARIANTS HPE3 ARG-31; GLY-117; ARG-117; GLU-224; THR-226 AND THR-383.
[11]	"Expression of the Sonic hedgehog (SHH) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly." Odent S., Atti-Bitach T., Blayau M., Mathieu M., Aug J., Delezo de A.L., Gall J.Y., Le Marec B., Munnich A., David V., Vekemans M. Hum. Mol. Genet. 8:1683-1689(1999) [PubMed: 10441331] [Abstract] Cited for: VARIANTS HPE3 HIS-100; GLN-188 AND ASN-222.
[12]	"The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly." Nanni L., Ming J.E., Bocian M., Steinhaus K., Bianchi D.W., Die-Smulders C., Giannotti A., Imaizumi K., Jones K.L., Campo M.D., Martin R.A., Meinecke P., Pierpont M.E.M., Robin N.H., Young I.D., Roessler E., Muenke M. Hum. Mol. Genet. 8:2479-2488(1999) [PubMed: 10556296] [Abstract] Cited for: VARIANTS HPE3 VAL-88; LYS-115; ARG-236; 263-ARG--ALA-269 DEL; ASP-290; ALA-424 AND LEU-436.
[13]	"SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature." Nanni L., Ming J.E., Du Y., Hall R.K., Aldred M., Bankier A., Muenke M. Am. J. Med. Genet. 102:1-10(2001) [PubMed: 11471164] [Abstract] Cited for: VARIANT SMMCI PHE-111.
[14]	"Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly." Orioli I.M., Castilla E.E.,

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References