Q14623 (IHH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Indian hedgehog protein
Short name=IHH

Alternative name(s):
HHG-2

Cleaved into the following 2 chains:

1. Indian hedgehog protein N-product
2. Indian hedgehog protein C-product

Gene names

Name:

IHH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	411 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.
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. Indian hedgehog protein C-product: Secreted › extracellular space By similarity. Note: The C-terminal peptide diffuses from the cell By similarity.
Tissue specificity	Expressed in embryonic lung, and in adult kidney and liver.
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 By similarity. Palmitoylated. N-palmitoylation is required for N-product multimerization and full activity. Ref.6
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.8 Ref.9 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.10
Sequence similarities	Belongs to the hedgehog family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Disease	Disease mutation
Domain	Signal
Molecular function	Developmental protein Hydrolase Protease
PTM	Autocatalytic cleavage Glycoprotein Lipoprotein Palmitate
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	bone resorption Inferred from electronic annotation. Source: Compara camera-type eye photoreceptor cell fate commitment Inferred from electronic annotation. Source: Compara cartilage development Inferred from electronic annotation. Source: Compara cell fate specification Inferred from electronic annotation. Source: Compara cell maturation Inferred from electronic annotation. Source: Compara cell-cell signaling Non-traceable author statement. Source: UniProtKB chondrocyte proliferation Inferred from electronic annotation. Source: Compara embryonic camera-type eye morphogenesis Inferred from electronic annotation. Source: Compara embryonic digestive tract morphogenesis Inferred from electronic annotation. Source: Compara embryonic pattern specification Inferred from electronic annotation. Source: Compara embryonic skeletal joint development Inferred from electronic annotation. Source: Compara epithelial cell morphogenesis Inferred from electronic annotation. Source: Compara epithelial cell-cell adhesion Inferred from electronic annotation. Source: Compara head morphogenesis Inferred from electronic annotation. Source: Compara heart looping Inferred from sequence or structural similarity. Source: BHF-UCL in utero embryonic development Inferred from electronic annotation. Source: Compara intein-mediated protein splicing Inferred from electronic annotation. Source: InterPro multicellular organism growth Inferred from electronic annotation. Source: Compara 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 eye pigmentation Inferred from electronic annotation. Source: Compara negative regulation of immature T cell proliferation in thymus Inferred from sequence or structural similarity. Source: BHF-UCL neuron development Inferred from electronic annotation. Source: Compara osteoblast differentiation Inferred from electronic annotation. Source: Compara pancreas development Inferred from electronic annotation. Source: Compara patterning of blood vessels Inferred from electronic annotation. Source: Compara 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 collagen biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of mesenchymal cell proliferation Inferred from electronic annotation. Source: Compara 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: Compara proteoglycan metabolic process Inferred from electronic annotation. Source: Compara proteolysis Inferred from electronic annotation. Source: UniProtKB-KW regulation of growth Inferred from electronic annotation. Source: Compara retinal pigment epithelium development Inferred from electronic annotation. Source: Compara smooth muscle tissue development Inferred from electronic annotation. Source: Compara smoothened signaling pathway Inferred from electronic annotation. Source: Compara somite development Inferred from sequence or structural similarity. Source: BHF-UCL vitelline membrane formation Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular matrix Inferred from electronic annotation. Source: Compara extracellular region Non-traceable author statement. Source: UniProtKB extracellular space Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	cholesterol binding Non-traceable author statement. Source: UniProtKB patched binding Non-traceable author statement. Source: UniProtKB peptidase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 27

27

Probable

Chain

28 – 411

384

Indian hedgehog protein

PRO_0000013229

Chain

28 – 202

175

Indian hedgehog protein N-product

PRO_0000013230

Chain

203 – 411

209

Indian hedgehog protein C-product

PRO_0000013231

Sites

Site

202 – 203

2

Cleavage; by autolysis By similarity

Site

248

1

Involved in cholesterol transfer By similarity

Site

272

1

Involved in auto-cleavage By similarity

Site

275

1

Essential for auto-cleavage By similarity

Amino acid modifications

Lipidation

28

1

N-palmitoyl cysteine Probable

Lipidation

202

1

Cholesterol glycine ester By similarity

Glycosylation

282

1

N-linked (GlcNAc...) Ref.7

Natural variations

Natural variant

46

1

P → L in ACFD. Ref.10

VAR_015981

Natural variant

95

1

E → K in BDA1. Ref.8

VAR_015982

Natural variant

100

1

D → E in BDA1. Ref.8

VAR_015983

Natural variant

100

1

D → N in BDA1. Ref.9
Corresponds to variant rs28936377 [ dbSNP | Ensembl ].

VAR_015984

Natural variant

131

1

E → K in BDA1. Ref.8

VAR_015985

Natural variant

190

1

V → A in ACFD. Ref.10

VAR_015986

Experimental info

Sequence conflict

100

1

D → R in AAA62178. Ref.4

Sequence conflict

246

1

F → L in BAA33523. Ref.1

Sequence conflict

309

1

V → A in BAA33523. Ref.1

Secondary structure

1

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411

Helix Strand Turn

Details...

Beta strand

52 – 56

5

Turn

61 – 64

4

Beta strand

73 – 75

3

Helix

76 – 80

5

Beta strand

89 – 91

3

Beta strand

96 – 98

3

Helix

99 – 101

3

Helix

105 – 121

17

Beta strand

127 – 131

5

Helix

144 – 147

4

Beta strand

150 – 155

6

Helix

160 – 162

3

Helix

163 – 172

10

Beta strand

176 – 182

7

Beta strand

185 – 189

5

Beta strand

193 – 195

3

Sequences

	Sequence		Length	Mass (Da)
	Q14623 [UniParc]. Last modified July 19, 2003. Version 4. Checksum: 4DA90C83F5ABF758	FASTA	411	45,251
	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

References

	« Hide 'large scale' referencesShow '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. , 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, MASS SPECTROMETRY. Tissue: Plasma.
[8]	"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.
[9]	"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.
[10]	"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

GeneReviews

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.

IPI

IPI00032190.

RefSeq

NP_002172.2. NM_002181.3.

UniGene

Hs.654504.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3K7G	X-ray	1.50	B	28-202	[»]
3K7H	X-ray	1.50	B	28-202	[»]
3K7I	X-ray	1.44	B	28-202	[»]
3K7J	X-ray	1.90	B	28-202	[»]
3N1F	X-ray	1.60	A/B	29-193	[»]
3N1M	X-ray	1.69	B	29-193	[»]
3N1O	X-ray	2.55	A/B/C	29-193	[»]
3N1P	X-ray	2.70	B	29-193	[»]

ProteinModelPortal

Q14623.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q14623. 1 interaction.

STRING

9606.ENSP00000295731.

Protein family/group databases

MEROPS

C46.003.

Polymorphism databases

DMDM

33112634.

Proteomic databases

PaxDb

Q14623.

PeptideAtlas

Q14623.

PRIDE

Q14623.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000295731; ENSP00000295731; ENSG00000163501.

GeneID

3549.

KEGG

hsa:3549.

UCSC

uc002vjo.2. human.

Organism-specific databases

CTD

3549.

GeneCards

GC02M219919.

H-InvDB

HIX0023995.

HGNC

HGNC:5956. IHH.

HPA

CAB009211.

MIM

112500. phenotype.
600726. gene.
607778. phenotype.

neXtProt

NX_Q14623.

Orphanet

63446. Acrocapitofemoral dysplasia.
93388. Brachydactyly type A1.

PharmGKB

PA29769.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG250647.

HOGENOM

HOG000233428.

HOVERGEN

HBG005480.

InParanoid

Q14623.

KO

K11989.

OMA

PGEGVHW.

OrthoDB

EOG46WZ8G.

PhylomeDB

Q14623.

Enzyme and pathway databases

Pathway_Interaction_DB

hedgehog_2pathway. Signaling events mediated by the Hedgehog family.

Gene expression databases

ArrayExpress

Q14623.

Bgee

Q14623.

CleanEx

HS_IHH.

Genevestigator

Q14623.

GermOnline

ENSG00000163501. Homo sapiens.

Family and domain databases

Gene3D

3.30.1380.10. 1 hit.

InterPro

IPR001657. Hedgehog.
IPR009045. Hedgehog_sig/DD-Pept_Zn-bd_dom.
IPR000320. Hedgehog_signaling_dom.
IPR001767. Hint_dom.
IPR003586. Hint_dom_C.
IPR003587. Hint_dom_N.
IPR006141. Intein_splice_site.
[Graphical view]

Pfam

PF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]

PIRSF

PIRSF009400. Peptidase_C46. 1 hit.

PRINTS

PR00632. SONICHHOG.

SMART

SM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]

SUPFAM

SSF55166. Hedgehog_sig_N. 1 hit.

PROSITE

PS50817. INTEIN_N_TER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q14623.

GenomeRNAi

3549.

NextBio

13856.

SOURCE

Search...

Entry information

Entry name

IHH_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 144 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.