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Protein

Indian hedgehog protein

Gene

IHH

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

Keywordsi

Molecular functionDevelopmental protein, Hydrolase, Protease
LigandCalcium, Metal-binding, Zinc

Enzyme and pathway databases

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
R-HSA-8941284 RUNX2 regulates chondrocyte maturation
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

EuPathDBiHostDB:ENSG00000163501.6
HGNCiHGNC:5956 IHH
MIMi600726 gene
neXtProtiNX_Q14623

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Brachydactyly A1 (BDA1)3 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 dbSNP:rs121917852Ensembl.1
Natural variantiVAR_015983100D → E in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917854Ensembl.1
Natural variantiVAR_015984100D → N in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917855Ensembl.1
Natural variantiVAR_015985131E → K in BDA1; no effect on the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917853Ensembl.1
Acrocapitofemoral dysplasia (ACFD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive 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 dbSNP:rs121917856Ensembl.1
Natural variantiVAR_015986190V → A in ACFD. 1 PublicationCorresponds to variant dbSNP:rs121917857Ensembl.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...) asparagine1 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

BioGridi1097651 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
OMAiRPEGKIT
OrthoDBiEOG091G0N90
PhylomeDBiQ14623
TreeFamiTF106458

Family and domain databases

Gene3Di3.30.1380.101 hit
InterProiView protein in InterPro
IPR001657 Hedgehog
IPR009045 Hedgehog_sig/DD-Pept_Zn-bd_sf
IPR000320 Hedgehog_signalling_dom
IPR001767 Hint_dom
IPR003586 Hint_dom_C
IPR003587 Hint_dom_N
IPR036844 Hint_dom_sf
IPR006141 Intein_N
PfamiView protein in Pfam
PF01085 HH_signal, 1 hit
PF01079 Hint, 1 hit
PIRSFiPIRSF009400 Peptidase_C46, 1 hit
PRINTSiPR00632 SONICHHOG
SMARTiView protein in SMART
SM00305 HintC, 1 hit
SM00306 HintN, 1 hit
SUPFAMiSSF51294 SSF51294, 1 hit
SSF55166 SSF55166, 1 hit
PROSITEiView protein in PROSITE
PS50817 INTEIN_N_TER, 1 hit

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 dbSNP:rs121917856Ensembl.1
Natural variantiVAR_01598295E → K in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917852Ensembl.1
Natural variantiVAR_015983100D → E in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917854Ensembl.1
Natural variantiVAR_015984100D → N in BDA1; decreases the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917855Ensembl.1
Natural variantiVAR_015985131E → K in BDA1; no effect on the stability of the indian hedgehog protein N-product. 2 PublicationsCorresponds to variant dbSNP:rs121917853Ensembl.1
Natural variantiVAR_015986190V → A in ACFD. 1 PublicationCorresponds to variant dbSNP:rs121917857Ensembl.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

Similar proteinsi

Entry informationi

Entry nameiIHH_HUMAN
AccessioniPrimary (citable) accession number: Q14623
Secondary accession number(s): B9EGM5, O43322, Q8N4B9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 19, 2003
Last modified: March 28, 2018
This is version 193 of the entry and version 4 of the sequence. See 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