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Protein

Indian hedgehog protein

Gene

IHH

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).By similarity1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi94Calcium 11 Publication1
Metal bindingi95Calcium 11 Publication1
Metal bindingi95Calcium 21 Publication1
Metal bindingi100Calcium 11 Publication1
Metal bindingi130Calcium 1; via carbonyl oxygen1 Publication1
Metal bindingi131Calcium 11 Publication1
Metal bindingi131Calcium 21 Publication1
Metal bindingi134Calcium 21 Publication1
Metal bindingi136Calcium 21 Publication1
Metal bindingi145Zinc2 Publications1
Metal bindingi152Zinc2 Publications1
Metal bindingi187Zinc2 Publications1
Sitei248Involved in cholesterol transferBy similarity1
Sitei272Involved in auto-cleavageBy similarity1
Sitei275Essential for auto-cleavageBy similarity1

GO - Molecular functioni

  • calcium ion binding Source: UniProtKB
  • patched binding Source: UniProtKB
  • peptidase activity Source: UniProtKB-KW

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Hydrolase, Protease

Keywords - Ligandi

Calcium, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000163501-MONOMER.
ReactomeiR-HSA-373080. Class B/2 (Secretin family receptors).
R-HSA-5358346. Hedgehog ligand biogenesis.
R-HSA-5362798. Release of Hh-Np from the secreting cell.
R-HSA-5632681. Ligand-receptor interactions.
R-HSA-5632684. Hedgehog 'on' state.
R-HSA-5635838. Activation of SMO.
R-HSA-5658034. HHAT G278V abrogates palmitoylation of Hh-Np.
SignaLinkiQ14623.
SIGNORiQ14623.

Protein family/group databases

MEROPSiC46.003.

Names & Taxonomyi

Protein namesi
Recommended name:
Indian hedgehog protein
Short name:
IHH
Alternative name(s):
HHG-2
Cleaved into the following 2 chains:
Gene namesi
Name:IHH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:5956. IHH.

Subcellular locationi

Indian hedgehog protein N-product :
Indian hedgehog protein C-product :

GO - Cellular componenti

  • extracellular space Source: UniProtKB-SubCell
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Brachydactyly A1 (BDA1)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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. BDA1 inheritance is autosomal dominant.
See also OMIM:112500
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01598295E → K in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917852dbSNPEnsembl.1
Natural variantiVAR_015983100D → E in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917854dbSNPEnsembl.1
Natural variantiVAR_015984100D → N in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs28936377dbSNPEnsembl.1
Natural variantiVAR_015985131E → K in BDA1; no effect on the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917853dbSNPEnsembl.1
Acrocapitofemoral dysplasia (ACFD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:607778
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01598146P → L in ACFD. 1 PublicationCorresponds to variant rs121917856dbSNPEnsembl.1
Natural variantiVAR_015986190V → A in ACFD. 1 PublicationCorresponds to variant rs121917857dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi95E → G: Increases the lysosomal degradation of the indian hedgehog protein N-product. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3549.
MalaCardsiIHH.
MIMi112500. phenotype.
607778. phenotype.
OpenTargetsiENSG00000163501.
Orphaneti63446. Acrocapitofemoral dysplasia.
93388. Brachydactyly type A1.
PharmGKBiPA29769.

Polymorphism and mutation databases

BioMutaiIHH.
DMDMi33112634.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 27CuratedAdd BLAST27
ChainiPRO_000001322928 – 411Indian hedgehog proteinAdd BLAST384
ChainiPRO_000001323028 – 202Indian hedgehog protein N-productAdd BLAST175
ChainiPRO_0000013231203 – 411Indian hedgehog protein C-productAdd BLAST209

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi28N-palmitoyl cysteine1 Publication1
Lipidationi202Cholesterol glycine esterBy similarity1
Glycosylationi282N-linked (GlcNAc...)1 Publication1

Post-translational modificationi

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).By similarity
Cholesterylation is required for N-product targeting to lipid rafts and multimerization.1 Publication
Palmitoylated. N-palmitoylation is required for N-product multimerization and full activity.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei202 – 203Cleavage; by autolysisBy similarity2

Keywords - PTMi

Autocatalytic cleavage, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

MaxQBiQ14623.
PaxDbiQ14623.
PeptideAtlasiQ14623.
PRIDEiQ14623.

PTM databases

iPTMnetiQ14623.
PhosphoSitePlusiQ14623.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000163501.
CleanExiHS_IHH.
GenevisibleiQ14623. HS.

Interactioni

Subunit structurei

Homooligomer (indian hedgehog protein N-product). Interacts with BOC and CDON. Interacts with PTCH1.2 Publications

GO - Molecular functioni

  • patched binding Source: UniProtKB

Protein-protein interaction databases

BioGridi109765. 1 interactor.
IntActiQ14623. 2 interactors.
STRINGi9606.ENSP00000295731.

Structurei

Secondary structure

1411
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi52 – 56Combined sources5
Turni61 – 64Combined sources4
Beta strandi73 – 75Combined sources3
Helixi76 – 80Combined sources5
Beta strandi89 – 91Combined sources3
Beta strandi96 – 98Combined sources3
Helixi99 – 101Combined sources3
Helixi105 – 121Combined sources17
Beta strandi127 – 131Combined sources5
Helixi144 – 147Combined sources4
Beta strandi150 – 155Combined sources6
Helixi160 – 162Combined sources3
Helixi163 – 172Combined sources10
Beta strandi176 – 182Combined sources7
Beta strandi185 – 189Combined sources5
Beta strandi193 – 195Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
ProteinModelPortaliQ14623.
SMRiQ14623.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ14623.

Family & Domainsi

Domaini

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.2 Publications

Sequence similaritiesi

Belongs to the hedgehog family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3638. Eukaryota.
ENOG410XQA3. LUCA.
GeneTreeiENSGT00390000001117.
HOGENOMiHOG000233428.
HOVERGENiHBG005480.
InParanoidiQ14623.
KOiK11989.
OMAiLGEGVHW.
OrthoDBiEOG091G0N90.
PhylomeDBiQ14623.
TreeFamiTF106458.

Family and domain databases

Gene3Di2.170.16.10. 1 hit.
3.30.1380.10. 1 hit.
InterProiIPR001657. Hedgehog.
IPR028992. Hedgehog/Intein_dom.
IPR009045. Hedgehog_sig/DD-Pept_Zn-bd_dom.
IPR000320. Hedgehog_signalling_dom.
IPR001767. Hint_dom.
IPR003586. Hint_dom_C.
IPR003587. Hint_dom_N.
IPR033385. IHH.
IPR006141. Intein_N.
[Graphical view]
PANTHERiPTHR11889:SF39. PTHR11889:SF39. 1 hit.
PfamiPF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]
PIRSFiPIRSF009400. Peptidase_C46. 1 hit.
PRINTSiPR00632. SONICHHOG.
SMARTiSM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]
SUPFAMiSSF51294. SSF51294. 1 hit.
SSF55166. SSF55166. 1 hit.
PROSITEiPS50817. INTEIN_N_TER. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q14623-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSPARLRPRL HFCLVLLLLL VVPAAWGCGP GRVVGSRRRP PRKLVPLAYK
60 70 80 90 100
QFSPNVPEKT LGASGRYEGK IARSSERFKE LTPNYNPDII FKDEENTGAD
110 120 130 140 150
RLMTQRCKDR LNSLAISVMN QWPGVKLRVT EGWDEDGHHS EESLHYEGRA
160 170 180 190 200
VDITTSDRDR NKYGLLARLA VEAGFDWVYY ESKAHVHCSV KSEHSAAAKT
210 220 230 240 250
GGCFPAGAQV RLESGARVAL SAVRPGDRVL AMGEDGSPTF SDVLIFLDRE
260 270 280 290 300
PHRLRAFQVI ETQDPPRRLA LTPAHLLFTA DNHTEPAARF RATFASHVQP
310 320 330 340 350
GQYVLVAGVP GLQPARVAAV STHVALGAYA PLTKHGTLVV EDVVASCFAA
360 370 380 390 400
VADHHLAQLA FWPLRLFHSL AWGSWTPGEG VHWYPQLLYR LGRLLLEEGS
410
FHPLGMSGAG S
Length:411
Mass (Da):45,251
Last modified:July 19, 2003 - v4
Checksum:i4DA90C83F5ABF758
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti100D → R in AAA62178 (PubMed:7590746).Curated1
Sequence conflicti246F → L in BAA33523 (Ref. 1) Curated1
Sequence conflicti309V → A in BAA33523 (Ref. 1) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01598146P → L in ACFD. 1 PublicationCorresponds to variant rs121917856dbSNPEnsembl.1
Natural variantiVAR_01598295E → K in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917852dbSNPEnsembl.1
Natural variantiVAR_015983100D → E in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917854dbSNPEnsembl.1
Natural variantiVAR_015984100D → N in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs28936377dbSNPEnsembl.1
Natural variantiVAR_015985131E → K in BDA1; no effect on the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant rs121917853dbSNPEnsembl.1
Natural variantiVAR_015986190V → A in ACFD. 1 PublicationCorresponds to variant rs121917857dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS33380.1.
RefSeqiNP_002172.2. NM_002181.3.
UniGeneiHs.654504.

Genome annotation databases

EnsembliENST00000295731; ENSP00000295731; ENSG00000163501.
GeneIDi3549.
KEGGihsa:3549.
UCSCiuc002vjo.3. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS33380.1.
RefSeqiNP_002172.2. NM_002181.3.
UniGeneiHs.654504.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
ProteinModelPortaliQ14623.
SMRiQ14623.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109765. 1 interactor.
IntActiQ14623. 2 interactors.
STRINGi9606.ENSP00000295731.

Protein family/group databases

MEROPSiC46.003.

PTM databases

iPTMnetiQ14623.
PhosphoSitePlusiQ14623.

Polymorphism and mutation databases

BioMutaiIHH.
DMDMi33112634.

Proteomic databases

MaxQBiQ14623.
PaxDbiQ14623.
PeptideAtlasiQ14623.
PRIDEiQ14623.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000295731; ENSP00000295731; ENSG00000163501.
GeneIDi3549.
KEGGihsa:3549.
UCSCiuc002vjo.3. human.

Organism-specific databases

CTDi3549.
DisGeNETi3549.
GeneCardsiIHH.
H-InvDBHIX0023995.
HGNCiHGNC:5956. IHH.
MalaCardsiIHH.
MIMi112500. phenotype.
600726. gene.
607778. phenotype.
neXtProtiNX_Q14623.
OpenTargetsiENSG00000163501.
Orphaneti63446. Acrocapitofemoral dysplasia.
93388. Brachydactyly type A1.
PharmGKBiPA29769.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3638. Eukaryota.
ENOG410XQA3. LUCA.
GeneTreeiENSGT00390000001117.
HOGENOMiHOG000233428.
HOVERGENiHBG005480.
InParanoidiQ14623.
KOiK11989.
OMAiLGEGVHW.
OrthoDBiEOG091G0N90.
PhylomeDBiQ14623.
TreeFamiTF106458.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000163501-MONOMER.
ReactomeiR-HSA-373080. Class B/2 (Secretin family receptors).
R-HSA-5358346. Hedgehog ligand biogenesis.
R-HSA-5362798. Release of Hh-Np from the secreting cell.
R-HSA-5632681. Ligand-receptor interactions.
R-HSA-5632684. Hedgehog 'on' state.
R-HSA-5635838. Activation of SMO.
R-HSA-5658034. HHAT G278V abrogates palmitoylation of Hh-Np.
SignaLinkiQ14623.
SIGNORiQ14623.

Miscellaneous databases

EvolutionaryTraceiQ14623.
GeneWikiiIHH_(protein).
GenomeRNAii3549.
PROiQ14623.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000163501.
CleanExiHS_IHH.
GenevisibleiQ14623. HS.

Family and domain databases

Gene3Di2.170.16.10. 1 hit.
3.30.1380.10. 1 hit.
InterProiIPR001657. Hedgehog.
IPR028992. Hedgehog/Intein_dom.
IPR009045. Hedgehog_sig/DD-Pept_Zn-bd_dom.
IPR000320. Hedgehog_signalling_dom.
IPR001767. Hint_dom.
IPR003586. Hint_dom_C.
IPR003587. Hint_dom_N.
IPR033385. IHH.
IPR006141. Intein_N.
[Graphical view]
PANTHERiPTHR11889:SF39. PTHR11889:SF39. 1 hit.
PfamiPF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]
PIRSFiPIRSF009400. Peptidase_C46. 1 hit.
PRINTSiPR00632. SONICHHOG.
SMARTiSM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]
SUPFAMiSSF51294. SSF51294. 1 hit.
SSF55166. SSF55166. 1 hit.
PROSITEiPS50817. INTEIN_N_TER. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiIHH_HUMAN
AccessioniPrimary (citable) accession number: Q14623
Secondary accession number(s): B9EGM5, O43322, Q8N4B9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 19, 2003
Last modified: November 30, 2016
This is version 181 of the entry and version 4 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.