IHH_CHICK
ID IHH_CHICK Reviewed; 408 AA.
AC Q98938;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Indian hedgehog protein {ECO:0000305};
DE Short=IHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE Contains:
DE RecName: Full=Indian hedgehog protein N-product;
DE Flags: Precursor;
GN Name=IHH {ECO:0000250|UniProtKB:Q14623};
OS Gallus gallus (Chicken).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae;
OC Phasianinae; Gallus.
OX NCBI_TaxID=9031;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=8662546; DOI=10.1126/science.273.5275.613;
RA Vortkamp A., Lee K., Lanske B., Segre G.V., Kronenberg H.M., Tabin C.J.;
RT "Regulation of rate of cartilage differentiation by Indian hedgehog and
RT PTH-related protein.";
RL Science 273:613-622(1996).
CC -!- FUNCTION: [Indian hedgehog protein]: The C-terminal part of the indian
CC hedgehog protein precursor displays an autoproteolysis and a
CC cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein into two parts
CC followed by the covalent attachment of a cholesterol moiety to the C-
CC terminal of the newly generated N-product (By similarity). Both
CC activities occur in the reticulum endoplasmic (By similarity).
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- FUNCTION: [Indian hedgehog protein N-product]: The dually lipidated
CC indian hedgehog protein N-product is a morphogen which is essential for
CC a variety of patterning events during development. Binds to the patched
CC (PTCH1) receptor, which functions in association with smoothened (SMO),
CC to activate the transcription of target genes (By similarity). Plays a
CC role in morphogenesis of the skeleton by coordinating growth and
CC differentiation of the endochondral skeleton. Positively regulates
CC PTHLH expression during endochondral bone formation preventing
CC chondrocyte hypertrophy. In contrast, participates in normal
CC chondrocyte proliferation in a PTHLH-independent pathway
CC (PubMed:8662546). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:8662546}.
CC -!- CATALYTIC ACTIVITY: [Indian hedgehog protein]:
CC Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]-
CC C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-
CC [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA-
CC COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135,
CC ChEBI:CHEBI:143140; Evidence={ECO:0000250|UniProtKB:Q62226};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505;
CC Evidence={ECO:0000250|UniProtKB:Q62226};
CC -!- SUBUNIT: [Indian hedgehog protein N-product]: Multimer.
CC {ECO:0000250|UniProtKB:Q14623}.
CC -!- SUBUNIT: Interacts with BOC and CDON. Interacts with PTCH1 (By
CC similarity). Interacts with glypican GPC3 (By similarity).
CC {ECO:0000250|UniProtKB:P97812, ECO:0000250|UniProtKB:Q14623}.
CC -!- SUBCELLULAR LOCATION: [Indian hedgehog protein N-product]: Cell
CC membrane {ECO:0000250|UniProtKB:Q14623}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q62226}. Note=The N-product remains associated
CC with the cell surface. {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBCELLULAR LOCATION: [Indian hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q15465}. Secreted
CC {ECO:0000250|UniProtKB:Q14623}. Note=Co-localizes with HHAT in the ER
CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
CC -!- TISSUE SPECIFICITY: Expressed in developing midgut, lung and cartilage
CC of developing long bones in the limb. {ECO:0000269|PubMed:8662546}.
CC -!- DOMAIN: [Indian hedgehog protein N-product]: Binds calcium and zinc
CC ions; this stabilizes the protein fold and is essential for protein-
CC protein interactions mediated by this domain.
CC {ECO:0000250|UniProtKB:Q14623}.
CC -!- PTM: [Indian hedgehog protein N-product]: Cholesterylation is required
CC for N-product targeting to lipid rafts and multimerization.
CC {ECO:0000250|UniProtKB:Q14623}.
CC -!- PTM: [Indian hedgehog protein]: The C-terminal domain displays an
CC autoproteolysis activity and a cholesterol transferase activity (By
CC similarity). Both activities result in the cleavage of the full-length
CC protein and covalent attachment of a cholesterol moiety to the C-
CC terminal of the newly generated N-product (By similarity). The N-
CC product is the active species in both local and long-range signaling,
CC whereas the C-product is degraded in the reticulum endoplasmic (By
CC similarity). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Indian hedgehog protein N-product]: N-palmitoylation by HHAT of
CC N-product is required for indian hedgehog protein N-product
CC multimerization and full activity. {ECO:0000250|UniProtKB:Q14623}.
CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
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DR EMBL; U58511; AAC60010.1; -; mRNA.
DR RefSeq; NP_990288.1; NM_204957.2.
DR AlphaFoldDB; Q98938; -.
DR SMR; Q98938; -.
DR STRING; 9031.ENSGALP00000018493; -.
DR MEROPS; C46.003; -.
DR PaxDb; Q98938; -.
DR Ensembl; ENSGALT00000018516; ENSGALP00000018493; ENSGALG00000011347.
DR GeneID; 395801; -.
DR KEGG; gga:395801; -.
DR CTD; 3549; -.
DR VEuPathDB; HostDB:geneid_395801; -.
DR eggNOG; KOG3638; Eukaryota.
DR GeneTree; ENSGT00940000159207; -.
DR InParanoid; Q98938; -.
DR OMA; APAVRGC; -.
DR OrthoDB; 1169356at2759; -.
DR PhylomeDB; Q98938; -.
DR PRO; PR:Q98938; -.
DR Proteomes; UP000000539; Chromosome 7.
DR Bgee; ENSGALG00000011347; Expressed in liver and 3 other tissues.
DR ExpressionAtlas; Q98938; baseline.
DR GO; GO:0031012; C:extracellular matrix; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IDA:AgBase.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central.
DR GO; GO:0005113; F:patched binding; ISS:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IEA:Ensembl.
DR GO; GO:0060220; P:camera-type eye photoreceptor cell fate commitment; IEA:Ensembl.
DR GO; GO:0051216; P:cartilage development; IEP:UniProtKB.
DR GO; GO:0001708; P:cell fate specification; IBA:GO_Central.
DR GO; GO:0048469; P:cell maturation; IEA:Ensembl.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0060591; P:chondroblast differentiation; IMP:AgBase.
DR GO; GO:0003413; P:chondrocyte differentiation involved in endochondral bone morphogenesis; IEA:Ensembl.
DR GO; GO:0035988; P:chondrocyte proliferation; IMP:AgBase.
DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IEA:Ensembl.
DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; IEA:Ensembl.
DR GO; GO:0042733; P:embryonic digit morphogenesis; ISS:AgBase.
DR GO; GO:0009880; P:embryonic pattern specification; IEA:Ensembl.
DR GO; GO:0072498; P:embryonic skeletal joint development; IEA:Ensembl.
DR GO; GO:0003382; P:epithelial cell morphogenesis; IEA:Ensembl.
DR GO; GO:0090136; P:epithelial cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0060323; P:head morphogenesis; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; IEA:Ensembl.
DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; IMP:AgBase.
DR GO; GO:1903042; P:negative regulation of chondrocyte hypertrophy; IMP:AgBase.
DR GO; GO:0048074; P:negative regulation of eye pigmentation; IEA:Ensembl.
DR GO; GO:0033088; P:negative regulation of immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0031016; P:pancreas development; IEA:Ensembl.
DR GO; GO:0010694; P:positive regulation of alkaline phosphatase activity; IDA:AgBase.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IEA:Ensembl.
DR GO; GO:0010770; P:positive regulation of cell morphogenesis involved in differentiation; IMP:AgBase.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:AgBase.
DR GO; GO:0007228; P:positive regulation of hh target transcription factor activity; IMP:AgBase.
DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IEA:Ensembl.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:AgBase.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IEA:Ensembl.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0030166; P:proteoglycan biosynthetic process; IMP:AgBase.
DR GO; GO:1902738; P:regulation of chondrocyte differentiation involved in endochondral bone morphogenesis; IMP:AgBase.
DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR GO; GO:1902733; P:regulation of growth plate cartilage chondrocyte differentiation; IMP:AgBase.
DR GO; GO:0003420; P:regulation of growth plate cartilage chondrocyte proliferation; IMP:AgBase.
DR GO; GO:0003406; P:retinal pigment epithelium development; IEA:Ensembl.
DR GO; GO:0048745; P:smooth muscle tissue development; IEA:Ensembl.
DR GO; GO:0007224; P:smoothened signaling pathway; IBA:GO_Central.
DR GO; GO:0061053; P:somite development; IEA:Ensembl.
DR GO; GO:0030704; P:vitelline membrane formation; IEA:Ensembl.
DR Gene3D; 3.30.1380.10; -; 1.
DR InterPro; IPR001657; Hedgehog.
DR InterPro; IPR001767; Hedgehog_Hint.
DR InterPro; IPR009045; Hedgehog_sig/DD-Pept_Zn-bd_sf.
DR InterPro; IPR000320; Hedgehog_signalling_dom.
DR InterPro; IPR003586; Hint_dom_C.
DR InterPro; IPR003587; Hint_dom_N.
DR InterPro; IPR036844; Hint_dom_sf.
DR InterPro; IPR033385; IHH.
DR PANTHER; PTHR11889:SF39; PTHR11889:SF39; 1.
DR Pfam; PF01085; HH_signal; 1.
DR Pfam; PF01079; Hint; 1.
DR PIRSF; PIRSF009400; Peptidase_C46; 1.
DR PRINTS; PR00632; SONICHHOG.
DR SMART; SM00305; HintC; 1.
DR SMART; SM00306; HintN; 1.
DR SUPFAM; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 1.
PE 2: Evidence at transcript level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Palmitate; Protease; Reference proteome; Secreted; Signal;
KW Zinc.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..408
FT /note="Indian hedgehog protein"
FT /id="PRO_0000013235"
FT CHAIN 24..198
FT /note="Indian hedgehog protein N-product"
FT /id="PRO_0000013236"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 96
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 130
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 148
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT SITE 198..199
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 244
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 268
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 271
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 24
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q14623"
FT LIPID 198
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
SQ SEQUENCE 408 AA; 44829 MW; BA397AE2A9357A24 CRC64;
MKPARLLLLL SGCALLLAPA VRCCGPGRVV GSRRRPPRKL IPLAYKQFSP NVPEKTLGAS
GRYEGKIARN SERFKELTPN YNPDIIFKDE ENTGADRLMT QRCKDRLNSL AISVMNQWPG
VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRNKYG MLARLAVEAG FDWVYYESKA
HIHCSVKSEH SAAAKTGGCF PGRALATLEN GARTPLWALR PGQRVLAMDG AGRPTYSDFL
AFLDKEPRAL TAFHVIETRQ PPRRLALTPT HLLFVADNAS APAAQFRPTF ASHVQPGHFV
LVAVGSGGLQ PAEVVGVRGR TDVGAYAPLT RHGTLVVDDV VASCFALVRE QQLAQMAFWP
LRLYHSLLGG PGVQGDGVHW YSGLLYRLGR MLLPPDSFHP LGAPRAES
