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 24-JAN-2024, entry version 149. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 9031-ENSGALP00000018493; -. DR Ensembl; ENSGALT00000018516; ENSGALP00000018493; ENSGALG00000011347. DR Ensembl; ENSGALT00010052149.1; ENSGALP00010031145.1; ENSGALG00010021505.1. DR Ensembl; ENSGALT00015053907; ENSGALP00015032215; ENSGALG00015022069. 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; 197397at2759; -. DR PhylomeDB; Q98938; -. DR Reactome; R-GGA-5358346; Hedgehog ligand biogenesis. DR Reactome; R-GGA-5362798; Release of Hh-Np from the secreting cell. DR Reactome; R-GGA-5632681; Ligand-receptor interactions. DR PRO; PR:Q98938; -. DR Proteomes; UP000000539; Chromosome 7. DR Bgee; ENSGALG00000011347; Expressed in liver and 3 other cell types or tissues. DR ExpressionAtlas; Q98938; baseline. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031012; C:extracellular matrix; IEA:Ensembl. DR GO; GO:0005615; C:extracellular space; IDA:AgBase. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central. DR GO; GO:0140853; F:cholesterol-protein transferase activity; ISS:UniProtKB. DR GO; GO:0005113; F:patched binding; ISS:UniProtKB. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB. 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; IEA:Ensembl. 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; IEA:Ensembl. 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: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:1902730; P:positive regulation of proteoglycan biosynthetic process; IMP:AgBase. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISS:UniProtKB. 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:0006029; P:proteoglycan metabolic process; IEA:Ensembl. 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:0097264; P:self proteolysis; ISS:UniProtKB. 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 CDD; cd00081; Hint; 1. DR Gene3D; 3.30.1380.10; -; 1. DR Gene3D; 2.170.16.10; Hedgehog/Intein (Hint) domain; 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 PANTHER; PTHR11889; HEDGEHOG; 1. DR PANTHER; PTHR11889:SF39; INDIAN HEDGEHOG PROTEIN; 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; SSF55166; Hedgehog/DD-peptidase; 1. DR SUPFAM; SSF51294; Hedgehog/intein (Hint) domain; 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 Transferase; 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 //