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Reviewed, UniProtKB/Swiss-Prot Q15465 (SHH_HUMAN)

Last modified November 25, 2008. Version 105. Feed 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

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length462 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

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: Secretedextracellular 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

Ontologies

Keywords

   Cellular componentCell membrane
Membrane
Secreted
   DiseaseDisease mutation
Holoprosencephaly
   DomainSignal
   Molecular functionDevelopmental protein
Hydrolase
Protease
   PTMAutocatalytic cleavage
Glycoprotein
Lipoprotein
Palmitate
   Technical termDirect protein sequencing

Gene Ontology (GO)

   Biological processandrogen 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 componentcell 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 functionlaminin-1 binding

Inferred from sequence or structural similarity. Source: UniProtKB

peptidase activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2323
Chain24 – 462439Sonic hedgehog protein
PRO_0000013208
Chain24 – 197174Sonic hedgehog protein N-product
PRO_0000013209
Chain198 – 462265Sonic hedgehog protein C-product
PRO_0000013210

Regions

Compositional bias407 – 4115Poly-Gly

Sites

Site197 – 1982Cleavage; by autolysis By similarity
Site2431Involved in cholesterol transfer By similarity
Site2671Involved in auto-cleavage By similarity
Site2701Essential for auto-cleavage By similarity

Amino acid modifications

Lipidation241N-palmitoyl cysteine
Lipidation1971Cholesterol glycine ester By similarity
Glycosylation2781N-linked (GlcNAc...)

Natural variations

Natural variant61R → T in HPE3.
VAR_023804
Natural variant271G → A in HPE3.
VAR_039888
Natural variant311G → R in HPE3. dbSNP rs28936675.
VAR_003619
Natural variant881D → V in HPE3; familial.
VAR_009163
Natural variant1001Q → H in HPE3; sporadic.
VAR_009164
Natural variant106 – 1072Missing in HPE3.
VAR_023805
Natural variant1101A → D in HPE3.
VAR_023806
Natural variant1111I → F in SMMCI.
VAR_017883
Natural variant1111I → N in HPE3.
VAR_039889
Natural variant1151N → K in HPE3; familial.
VAR_009165
Natural variant1171W → G in HPE3.
VAR_003620
Natural variant1171W → R in HPE3.
VAR_003621
Natural variant1401H → P in HPE3.
VAR_039890
Natural variant1401H → Q in HPE3.
VAR_039891
Natural variant1501T → R in HPE3.
VAR_023807
Natural variant176 – 1783Missing in HPE3.
VAR_023808
Natural variant1831C → F in HPE3.
VAR_039892
Natural variant1881E → Q in HPE3; familial.
VAR_009166
Natural variant2221D → N in HPE3; familial.
VAR_009167
Natural variant2241V → E in HPE3.
VAR_009168
Natural variant2261A → T in HPE3; familial.
VAR_009169
Natural variant2361S → R in HPE3; familial.
VAR_009170
Natural variant263 – 2697Missing in HPE3; sporadic.
VAR_009171
Natural variant2671T → I in HPE3.
VAR_039893
Natural variant2711L → P in HPE3.
VAR_023809
Natural variant2901G → D in HPE3; sporadic.
VAR_009172
Natural variant3321V → A in HPE3.
VAR_023810
Natural variant3471P → Q in HPE3.
VAR_023811
Natural variant3541I → T in HPE3.
VAR_023812
Natural variant3731A → T in HPE3.
VAR_039894
Natural variant378 – 3803Missing in HPE3; familial.
VAR_009173
Natural variant3811R → P in HPE3.
VAR_023813
Natural variant3831A → T in HPE3; sporadic.
VAR_009174
Natural variant401 – 4088Missing in ocular coloboma.
VAR_017884
Natural variant404 – 4085Missing in HPE3; familial.
VAR_009175
Natural variant4241P → A in HPE3; familial.
VAR_009176
Natural variant4361S → L in HPE3; sporadic.
VAR_009177

Experimental info

Mutagenesis241C → S: Abolishes palmitoylation

Sequences

Sequence LengthMass (Da)Tools
Q15465-1 [UniParc].

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

FASTA46249,607
        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 

« Hide

References

« Hide 'large scale' references
[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. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., 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.,