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Q14623 (IHH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 153. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Indian hedgehog protein

Short name=IHH
Alternative name(s):
HHG-2
Gene names
Name:IHH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length411 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Intercellular signal essential for a variety of patterning events during development. Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Implicated in endochondral ossification: may regulate the balance between growth and ossification of the developing bones. Induces the expression of parathyroid hormone-related protein (PTHRP) By similarity. Ref.9

Subunit structure

Homooligomer (indian hedgehog protein N-product). Interacts with BOC and CDON. Interacts with PTCH1. Ref.8 Ref.9

Subcellular location

Indian hedgehog protein N-product: Cell membrane; Lipid-anchor; Extracellular side By similarity. Note: The N-terminal peptide remains associated with the cell surface By similarity. Ref.9

Indian hedgehog protein C-product: Secretedextracellular space By similarity. Note: The C-terminal peptide diffuses from the cell By similarity. Ref.9

Cell membrane Ref.9.

Tissue specificity

Expressed in embryonic lung, and in adult kidney and liver.

Domain

The indian hedgehog protein N-product binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain. Ref.8 Ref.9

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 By similarity.

Cholesterylation is required for N-product targeting to lipid rafts and multimerization.

Palmitoylated. N-palmitoylation is required for N-product multimerization and full activity. Ref.6 Ref.9

Involvement in disease

Brachydactyly A1 (BDA1) [MIM:112500]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type A1 is characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9 Ref.10 Ref.11

Acrocapitofemoral dysplasia (ACFD) [MIM:607778]: A disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses are also present to a variable extent at the shoulders, knees and ankles.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12

Sequence similarities

Belongs to the hedgehog family.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   DiseaseDisease mutation
   DomainSignal
   LigandCalcium
Metal-binding
Zinc
   Molecular functionDevelopmental protein
Hydrolase
Protease
   PTMAutocatalytic cleavage
Glycoprotein
Lipoprotein
Palmitate
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbone resorption

Inferred from electronic annotation. Source: Ensembl

camera-type eye photoreceptor cell fate commitment

Inferred from electronic annotation. Source: Ensembl

cartilage development

Inferred from electronic annotation. Source: Ensembl

cell fate specification

Inferred from electronic annotation. Source: Ensembl

cell maturation

Inferred from electronic annotation. Source: Ensembl

cell-cell signaling

Inferred from electronic annotation. Source: InterPro

chondrocyte proliferation

Inferred from electronic annotation. Source: Ensembl

embryonic camera-type eye morphogenesis

Inferred from electronic annotation. Source: Ensembl

embryonic digestive tract morphogenesis

Inferred from electronic annotation. Source: Ensembl

embryonic pattern specification

Inferred from electronic annotation. Source: Ensembl

embryonic skeletal joint development

Inferred from electronic annotation. Source: Ensembl

epithelial cell morphogenesis

Inferred from electronic annotation. Source: Ensembl

epithelial cell-cell adhesion

Inferred from electronic annotation. Source: Ensembl

head morphogenesis

Inferred from electronic annotation. Source: Ensembl

heart looping

Inferred from sequence or structural similarity. Source: BHF-UCL

in utero embryonic development

Inferred from electronic annotation. Source: Ensembl

intein-mediated protein splicing

Inferred from electronic annotation. Source: InterPro

maternal process involved in female pregnancy

Inferred from electronic annotation. Source: Ensembl

multicellular organism growth

Inferred from electronic annotation. Source: Ensembl

negative regulation of T cell differentiation in thymus

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of alpha-beta T cell differentiation

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of eye pigmentation

Inferred from electronic annotation. Source: Ensembl

negative regulation of immature T cell proliferation in thymus

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of signal transduction

Inferred from electronic annotation. Source: Ensembl

neuron development

Inferred from electronic annotation. Source: Ensembl

osteoblast differentiation

Inferred from electronic annotation. Source: Ensembl

pancreas development

Inferred from electronic annotation. Source: Ensembl

patterning of blood vessels

Inferred from electronic annotation. Source: Ensembl

positive regulation of T cell differentiation in thymus

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of alpha-beta T cell differentiation

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of chondrocyte differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of collagen biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of epithelial cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of mesenchymal cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of smoothened signaling pathway

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

proteoglycan metabolic process

Inferred from electronic annotation. Source: Ensembl

proteolysis

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of growth

Inferred from electronic annotation. Source: Ensembl

response to estradiol

Inferred from electronic annotation. Source: Ensembl

retinal pigment epithelium development

Inferred from electronic annotation. Source: Ensembl

skeletal system development

Inferred from mutant phenotype Ref.9. Source: UniProtKB

smooth muscle tissue development

Inferred from electronic annotation. Source: Ensembl

smoothened signaling pathway

Inferred from direct assay Ref.9. Source: UniProtKB

somite development

Inferred from sequence or structural similarity. Source: BHF-UCL

vitelline membrane formation

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentextracellular matrix

Inferred from electronic annotation. Source: Ensembl

extracellular space

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from direct assay Ref.9. Source: UniProtKB

   Molecular_functioncalcium ion binding

Inferred from direct assay Ref.9. Source: UniProtKB

patched binding

Inferred from physical interaction Ref.9. Source: UniProtKB

peptidase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2727 Probable
Chain28 – 411384Indian hedgehog protein
PRO_0000013229
Chain28 – 202175Indian hedgehog protein N-product
PRO_0000013230
Chain203 – 411209Indian hedgehog protein C-product
PRO_0000013231

Sites

Metal binding941Calcium 1
Metal binding951Calcium 1
Metal binding951Calcium 2
Metal binding1001Calcium 1
Metal binding1301Calcium 1; via carbonyl oxygen
Metal binding1311Calcium 1
Metal binding1311Calcium 2
Metal binding1341Calcium 2
Metal binding1361Calcium 2
Metal binding1451Zinc
Metal binding1521Zinc
Metal binding1871Zinc
Site202 – 2032Cleavage; by autolysis By similarity
Site2481Involved in cholesterol transfer By similarity
Site2721Involved in auto-cleavage By similarity
Site2751Essential for auto-cleavage By similarity

Amino acid modifications

Lipidation281N-palmitoyl cysteine Probable
Lipidation2021Cholesterol glycine ester By similarity
Glycosylation2821N-linked (GlcNAc...) Ref.7

Natural variations

Natural variant461P → L in ACFD. Ref.12
VAR_015981
Natural variant951E → K in BDA1; decreases the stability of the indian hedgehog protein N-product. Ref.9 Ref.10
VAR_015982
Natural variant1001D → E in BDA1; decreases the stability of the indian hedgehog protein N-product. Ref.9 Ref.10
VAR_015983
Natural variant1001D → N in BDA1; decreases the stability of the indian hedgehog protein N-product. Ref.9 Ref.11
Corresponds to variant rs28936377 [ dbSNP | Ensembl ].
VAR_015984
Natural variant1311E → K in BDA1; no effect on the stability of the indian hedgehog protein N-product. Ref.9 Ref.10
VAR_015985
Natural variant1901V → A in ACFD. Ref.12
VAR_015986

Experimental info

Mutagenesis951E → G: Increases the lysosomal degradation of the indian hedgehog protein N-product. Ref.9
Sequence conflict1001D → R in AAA62178. Ref.4
Sequence conflict2461F → L in BAA33523. Ref.1
Sequence conflict3091V → A in BAA33523. Ref.1

Secondary structure

.............................. 411
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q14623 [UniParc].

Last modified July 19, 2003. Version 4.
Checksum: 4DA90C83F5ABF758

FASTA41145,251
        10         20         30         40         50         60 
MSPARLRPRL HFCLVLLLLL VVPAAWGCGP GRVVGSRRRP PRKLVPLAYK QFSPNVPEKT 

        70         80         90        100        110        120 
LGASGRYEGK IARSSERFKE LTPNYNPDII FKDEENTGAD RLMTQRCKDR LNSLAISVMN 

       130        140        150        160        170        180 
QWPGVKLRVT EGWDEDGHHS EESLHYEGRA VDITTSDRDR NKYGLLARLA VEAGFDWVYY 

       190        200        210        220        230        240 
ESKAHVHCSV KSEHSAAAKT GGCFPAGAQV RLESGARVAL SAVRPGDRVL AMGEDGSPTF 

       250        260        270        280        290        300 
SDVLIFLDRE PHRLRAFQVI ETQDPPRRLA LTPAHLLFTA DNHTEPAARF RATFASHVQP 

       310        320        330        340        350        360 
GQYVLVAGVP GLQPARVAAV STHVALGAYA PLTKHGTLVV EDVVASCFAA VADHHLAQLA 

       370        380        390        400        410 
FWPLRLFHSL AWGSWTPGEG VHWYPQLLYR LGRLLLEEGS FHPLGMSGAG S 

« Hide

References

« Hide 'large scale' references
[1]"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].
[2]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Testis.
[4]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 100-411.
Tissue: Fetal lung.
[5]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE OF 124-172.
[6]"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] [Europe PMC] [Abstract]
Cited for: PALMITOYLATION AT CYS-28.
[7]"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] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-282.
Tissue: Plasma.
[8]"All mammalian Hedgehog proteins interact with cell adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner."
Kavran J.M., Ward M.D., Oladosu O.O., Mulepati S., Leahy D.J.
J. Biol. Chem. 285:24584-24590(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 29-193 IN COMPLEXES WITH CALCIUM IONS; ZINC IONS; BOC AND CDON, DOMAIN, INTERACTION WITH BOC AND CDON.
[9]"Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels."
Ma G., Yu J., Xiao Y., Chan D., Gao B., Hu J., He Y., Guo S., Zhou J., Zhang L., Gao L., Zhang W., Kang Y., Cheah K.S., Feng G., Guo X., Wang Y., Zhou C.Z., He L.
Cell Res. 21:1343-1357(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.44 ANGSTROMS) OF 28-202 OF WILD TYPE AND VARIANTS BDA1 LYS-95; GLU-100 AND LYS-131 IN COMPLEX WITH ZINC IONS, FUNCTION, SUBUNIT, INTERACTION WITH PTCH1, SUBCELLULAR LOCATION, CHOLESTERYLATION, PALMITOYLATION, MUTAGENESIS OF GLU-95, DOMAIN, CHARACTERIZATION OF VARIANTS BDA1 LYS-95; ASN-100; GLU-100 AND LYS-131.
[10]"Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1."
Gao B., Guo J., She C., Shu A., Yang M., Tan Z., Yang X., Guo S., Feng G., He L.
Nat. Genet. 28:386-388(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS BDA1 LYS-95; GLU-100 AND LYS-131.
[11]"A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved."
McCready M.E., Sweeney E., Fryer A.E., Donnai D., Baig A., Racacho L., Warman M.L., Hunter A.G.W., Bulman D.E.
Hum. Genet. 111:368-375(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT BDA1 ASN-100.
[12]"Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips."
Hellemans J., Coucke P.J., Giedion A., De Paepe A., Kramer P., Beemer F., Mortier G.R.
Am. J. Hum. Genet. 72:1040-1046(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ACFD LEU-46 AND ALA-190.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB018076 Genomic DNA. Translation: BAA33523.2.
CH471063 Genomic DNA. Translation: EAW70675.1.
BC034757 mRNA. Translation: AAH34757.2.
BC136587 mRNA. Translation: AAI36588.1.
BC136588 mRNA. Translation: AAI36589.1.
L38517 mRNA. Translation: AAA62178.1.
RefSeqNP_002172.2. NM_002181.3.
UniGeneHs.654504.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3K7GX-ray1.50B28-202[»]
3K7HX-ray1.50B28-202[»]
3K7IX-ray1.44B28-202[»]
3K7JX-ray1.90B28-202[»]
3N1FX-ray1.60A/B29-193[»]
3N1MX-ray1.69B29-193[»]
3N1OX-ray2.55A/B/C29-193[»]
3N1PX-ray2.70B29-193[»]
ProteinModelPortalQ14623.
SMRQ14623. Positions 41-197, 203-349.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109765. 3 interactions.
IntActQ14623. 1 interaction.
STRING9606.ENSP00000295731.

Protein family/group databases

MEROPSC46.003.

Polymorphism databases

DMDM33112634.

Proteomic databases

PaxDbQ14623.
PeptideAtlasQ14623.
PRIDEQ14623.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000295731; ENSP00000295731; ENSG00000163501.
GeneID3549.
KEGGhsa:3549.
UCSCuc002vjo.2. human.

Organism-specific databases

CTD3549.
GeneCardsGC02M219919.
H-InvDBHIX0023995.
HGNCHGNC:5956. IHH.
HPACAB009211.
MIM112500. phenotype.
600726. gene.
607778. phenotype.
neXtProtNX_Q14623.
Orphanet63446. Acrocapitofemoral dysplasia.
93388. Brachydactyly type A1.
PharmGKBPA29769.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG250647.
HOGENOMHOG000233428.
HOVERGENHBG005480.
InParanoidQ14623.
KOK11989.
OMAPGEGVHW.
OrthoDBEOG779NZ5.
PhylomeDBQ14623.
TreeFamTF106458.

Enzyme and pathway databases

SignaLinkQ14623.

Gene expression databases

ArrayExpressQ14623.
BgeeQ14623.
CleanExHS_IHH.
GenevestigatorQ14623.

Family and domain databases

Gene3D3.30.1380.10. 1 hit.
InterProIPR001657. Hedgehog.
IPR009045. Hedgehog_sig/DD-Pept_Zn-bd_dom.
IPR000320. Hedgehog_signalling_dom.
IPR001767. Hint_dom.
IPR003586. Hint_dom_C.
IPR003587. Hint_dom_N.
IPR006141. Intein_splice_site.
[Graphical view]
PfamPF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]
PIRSFPIRSF009400. Peptidase_C46. 1 hit.
PRINTSPR00632. SONICHHOG.
SMARTSM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]
SUPFAMSSF55166. SSF55166. 1 hit.
PROSITEPS50817. INTEIN_N_TER. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ14623.
GeneWikiIHH_(protein).
GenomeRNAi3549.
NextBio13856.
PROQ14623.
SOURCESearch...

Entry information

Entry nameIHH_HUMAN
AccessionPrimary (citable) accession number: Q14623
Secondary accession number(s): B9EGM5, O43322, Q8N4B9
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 19, 2003
Last modified: April 16, 2014
This is version 153 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM