ID SHH_RAT Reviewed; 437 AA. AC Q63673; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 178. DE RecName: Full=Sonic hedgehog protein {ECO:0000305}; DE Short=SHH; DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226}; DE AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000250|UniProtKB:Q62226}; DE Short=ShhNC {ECO:0000250|UniProtKB:Q62226}; DE Contains: DE RecName: Full=Sonic hedgehog protein N-product; DE Short=ShhN; DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000250|UniProtKB:Q62226}; DE Short=ShhNp {ECO:0000250|UniProtKB:Q62226}; DE Flags: Precursor; GN Name=Shh {ECO:0000312|RGD:3673}; Synonyms=Vhh-1; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC STRAIN=Sprague-Dawley; TISSUE=Embryonic floor plate; RX PubMed=8124714; DOI=10.1016/0092-8674(94)90514-2; RA Roelink H., Augsburger A., Heemskerk J., Korzh V., Norlin S., RA Ruiz i Altaba A., Tanabe Y., Placzek M., Edlund T., Jessell T.M., Dodd J.; RT "Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of RT hedgehog expressed by the notochord."; RL Cell 76:761-775(1994). RN [2] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=11395778; DOI=10.1038/35079648; RA Zeng X., Goetz J.A., Suber L.M., Scott W.J. Jr., Schreiner C.M., RA Robbins D.J.; RT "A freely diffusible form of Sonic hedgehog mediates long-range RT signalling."; RL Nature 411:716-720(2001). CC -!- FUNCTION: [Sonic hedgehog protein]: The C-terminal part of the sonic 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 (ShhN CC and ShhC) followed by the covalent attachment of a cholesterol moiety CC to the C-terminal of the newly generated ShhN (By similarity). Both CC activities occur in the reticulum endoplasmic (By similarity). Once CC cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity). CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}. CC -!- FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated CC sonic hedgehog protein N-product (ShhNp) is a morphogen which is CC essential for a variety of patterning events during development. CC Induces ventral cell fate in the neural tube and somites (By CC similarity). Involved in the patterning of the anterior-posterior axis CC of the developing limb bud (By similarity). Essential for axon guidance CC (By similarity). Binds to the patched (PTCH1) receptor, which functions CC in association with smoothened (SMO), to activate the transcription of CC target genes (By similarity). In the absence of SHH, PTCH1 represses CC the constitutive signaling activity of SMO (By similarity). CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}. CC -!- CATALYTIC ACTIVITY: [Sonic 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: Interacts with HHATL/GUP1 which negatively regulates HHAT- CC mediated palmitoylation of the SHH N-terminus (By similarity). CC Interacts with BOC and CDON (By similarity). Interacts with HHIP (By CC similarity). Interacts with DISP1 via its cholesterol anchor (By CC similarity). Interacts with SCUBE2 (By similarity). Interacts with CC glypican GPC3 (By similarity). {ECO:0000250|UniProtKB:Q15465, CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:11395778}. CC -!- SUBUNIT: [Sonic hedgehog protein N-product]: Multimer. CC {ECO:0000250|UniProtKB:Q15465}. CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane CC {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in the ER CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}. CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Cell membrane CC {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor CC {ECO:0000250|UniProtKB:Q62226}. Note=The dual-lipidated sonic hedgehog CC protein N-product (ShhNp) is firmly tethered to the cell membrane where CC it forms multimers (By similarity). Further solubilization and release CC from the cell surface seem to be achieved through different mechanisms, CC including the interaction with DISP1 and SCUBE2, movement by CC lipoprotein particles, transport by cellular extensions called CC cytonemes or by the proteolytic removal of both terminal lipidated CC peptides. {ECO:0000250|UniProtKB:Q62226}. CC -!- TISSUE SPECIFICITY: Expressed in the node, notochord, floor plate, and CC posterior limb bud mesenchyme. {ECO:0000269|PubMed:8124714}. CC -!- DOMAIN: [Sonic 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:Q62226}. CC -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW) CC motif is required for heparan sulfate binding of the solubilized ShhNp CC (By similarity). The N-terminal palmitoylated peptide is cleaved at the CC Heparan sulfate-binding Cardin-Weintraub (CW) motif site (By CC similarity). The cleavage reduced the interactions with heparan CC sulfate. The cleavage is enhanced by SCUBE2 (By similarity). CC {ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Sonic 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-terminal fragment (ShhN) (By CC similarity). Cholesterylation is required for the sonic hedgehog CC protein N-product targeting to lipid rafts and multimerization (By CC similarity). ShhN is the active species in both local and long-range CC signaling, whereas the C-product (ShhC) is degraded in the reticulum CC endoplasmic (By similarity). {ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Sonic hedgehog protein N-product]: N-palmitoylation by HHAT of CC ShhN is required for sonic hedgehog protein N-product multimerization CC and full activity (By similarity). It is a prerequisite for the CC membrane-proximal positioning and the subsequent shedding of this N- CC terminal peptide (By similarity). {ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C- CC terminal peptides of ShhNp can be cleaved (shedding) (By similarity). CC The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub CC (CW) motif site (By similarity). The cleavage reduced the interactions CC with heparan sulfate (By similarity). The cleavage is enhanced by CC SCUBE2 (By similarity). {ECO:0000250|UniProtKB:Q62226}. CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}. CC -!- CAUTION: The several steps and mechanisms that permit controlled Shh CC dispersion and gradient formation remain controversial. The ShhNC C- CC terminal domain displays an autoproteolysis activity and a cholesterol CC transferase activity resulting in the cleavage and covalent attachment CC of a cholesterol moiety to the C-terminal of the newly generated N- CC terminal fragment (ShhN). The protein is further modified by covalent CC addition of palmitate at the N-terminal of ShhN, resulting to the dual- CC lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane CC where it forms multimers. Further solubilization and release from the CC cell surface seem to be achieved through different mechanisms, CC including the interaction with DISP1 and SCUBE2, movement by CC lipoprotein particles, transport by cellular extensions called CC cytonemes or by proteolytic removal of both terminal lipidated CC peptides. Once released, the fully processed Shh can signal within CC embryonic tissues both at short and long-range. CC {ECO:0000250|UniProtKB:Q62226}. 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; L27340; AAA20999.1; -; mRNA. DR PIR; B53193; B53193. DR RefSeq; NP_058917.1; NM_017221.1. DR AlphaFoldDB; Q63673; -. DR SMR; Q63673; -. DR STRING; 10116.ENSRNOP00000008497; -. DR MEROPS; C46.002; -. DR GlyCosmos; Q63673; 1 site, No reported glycans. DR GlyGen; Q63673; 1 site. DR PhosphoSitePlus; Q63673; -. DR PaxDb; 10116-ENSRNOP00000008497; -. DR GeneID; 29499; -. DR KEGG; rno:29499; -. DR AGR; RGD:3673; -. DR CTD; 6469; -. DR RGD; 3673; Shh. DR eggNOG; KOG3638; Eukaryota. DR InParanoid; Q63673; -. DR OrthoDB; 197397at2759; -. DR PhylomeDB; Q63673; -. DR Reactome; R-RNO-5358346; Hedgehog ligand biogenesis. DR Reactome; R-RNO-5362798; Release of Hh-Np from the secreting cell. DR Reactome; R-RNO-5632681; Ligand-receptor interactions. DR Reactome; R-RNO-5635838; Activation of SMO. DR PRO; PR:Q63673; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0030424; C:axon; IDA:RGD. DR GO; GO:0009986; C:cell surface; ISS:UniProtKB. DR GO; GO:0030425; C:dendrite; IDA:RGD. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031012; C:extracellular matrix; ISO:RGD. DR GO; GO:0005615; C:extracellular space; IDA:RGD. DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; ISO:RGD. DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IDA:RGD. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0008021; C:synaptic vesicle; IDA:RGD. DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB. DR GO; GO:0140853; F:cholesterol-protein transferase activity; ISS:UniProtKB. DR GO; GO:0005539; F:glycosaminoglycan binding; ISO:RGD. DR GO; GO:0043237; F:laminin-1 binding; ISS:UniProtKB. DR GO; GO:0005113; F:patched binding; ISS:UniProtKB. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0046632; P:alpha-beta T cell differentiation; ISO:RGD. DR GO; GO:0048856; P:anatomical structure development; ISO:RGD. DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; ISO:RGD. DR GO; GO:0008209; P:androgen metabolic process; ISS:UniProtKB. DR GO; GO:0001525; P:angiogenesis; ISO:RGD. DR GO; GO:0048645; P:animal organ formation; ISO:RGD. DR GO; GO:0009952; P:anterior/posterior pattern specification; ISO:RGD. DR GO; GO:0097190; P:apoptotic signaling pathway; ISS:UniProtKB. DR GO; GO:0060840; P:artery development; ISO:RGD. DR GO; GO:0048708; P:astrocyte differentiation; ISO:RGD. DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB. DR GO; GO:0060020; P:Bergmann glial cell differentiation; ISO:RGD. DR GO; GO:0007596; P:blood coagulation; ISO:RGD. DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; ISS:UniProtKB. DR GO; GO:0060442; P:branching involved in prostate gland morphogenesis; ISO:RGD. DR GO; GO:0060445; P:branching involved in salivary gland morphogenesis; ISO:RGD. DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; ISS:UniProtKB. DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; ISS:UniProtKB. DR GO; GO:0060447; P:bud outgrowth involved in lung branching; ISO:RGD. DR GO; GO:0043010; P:camera-type eye development; ISO:RGD. DR GO; GO:0060070; P:canonical Wnt signaling pathway; ISO:RGD. DR GO; GO:0043369; P:CD4-positive or CD8-positive, alpha-beta T cell lineage commitment; ISS:UniProtKB. DR GO; GO:0048468; P:cell development; ISS:UniProtKB. DR GO; GO:0045165; P:cell fate commitment; ISO:RGD. DR GO; GO:0001708; P:cell fate specification; ISS:UniProtKB. DR GO; GO:0016477; P:cell migration; ISO:RGD. DR GO; GO:0008283; P:cell population proliferation; ISO:RGD. DR GO; GO:0021924; P:cell proliferation in external granule layer; ISO:RGD. DR GO; GO:0007267; P:cell-cell signaling; ISS:UniProtKB. DR GO; GO:0071285; P:cellular response to lithium ion; ISO:RGD. DR GO; GO:0007417; P:central nervous system development; ISS:UniProtKB. DR GO; GO:0021930; P:cerebellar granule cell precursor proliferation; ISS:UniProtKB. DR GO; GO:0071679; P:commissural neuron axon guidance; IMP:RGD. DR GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; ISO:RGD. DR GO; GO:0007368; P:determination of left/right symmetry; ISO:RGD. DR GO; GO:0048589; P:developmental growth; ISO:RGD. DR GO; GO:0007502; P:digestive tract mesoderm development; IDA:RGD. DR GO; GO:0048546; P:digestive tract morphogenesis; ISO:RGD. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; ISO:RGD. DR GO; GO:0009953; P:dorsal/ventral pattern formation; ISS:UniProtKB. DR GO; GO:0007398; P:ectoderm development; ISO:RGD. DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; ISO:RGD. DR GO; GO:0042733; P:embryonic digit morphogenesis; ISS:UniProtKB. DR GO; GO:0048617; P:embryonic foregut morphogenesis; ISO:RGD. DR GO; GO:0035115; P:embryonic forelimb morphogenesis; ISO:RGD. DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; ISO:RGD. DR GO; GO:0030326; P:embryonic limb morphogenesis; ISS:UniProtKB. DR GO; GO:0048598; P:embryonic morphogenesis; ISO:RGD. DR GO; GO:0048568; P:embryonic organ development; ISO:RGD. DR GO; GO:0048706; P:embryonic skeletal system development; ISO:RGD. DR GO; GO:0006897; P:endocytosis; ISO:RGD. DR GO; GO:0050673; P:epithelial cell proliferation; ISO:RGD. DR GO; GO:0060767; P:epithelial cell proliferation involved in prostate gland development; ISO:RGD. DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; ISO:RGD. DR GO; GO:0060441; P:epithelial tube branching involved in lung morphogenesis; IEP:RGD. DR GO; GO:0060684; P:epithelial-mesenchymal cell signaling; ISO:RGD. DR GO; GO:0060738; P:epithelial-mesenchymal signaling involved in prostate gland development; ISO:RGD. DR GO; GO:0090162; P:establishment of epithelial cell polarity; ISO:RGD. DR GO; GO:0030900; P:forebrain development; ISS:UniProtKB. DR GO; GO:0021871; P:forebrain regionalization; ISO:RGD. DR GO; GO:0048859; P:formation of anatomical boundary; ISO:RGD. DR GO; GO:0061196; P:fungiform papilla development; IMP:RGD. DR GO; GO:0061198; P:fungiform papilla formation; IMP:RGD. DR GO; GO:0061197; P:fungiform papilla morphogenesis; IMP:RGD. DR GO; GO:0010467; P:gene expression; ISO:RGD. DR GO; GO:0001942; P:hair follicle development; ISO:RGD. DR GO; GO:0031069; P:hair follicle morphogenesis; ISO:RGD. DR GO; GO:0007507; P:heart development; ISS:UniProtKB. DR GO; GO:0001947; P:heart looping; ISO:RGD. DR GO; GO:0030902; P:hindbrain development; ISS:UniProtKB. DR GO; GO:0007442; P:hindgut morphogenesis; ISO:RGD. DR GO; GO:0048839; P:inner ear development; ISO:RGD. DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro. DR GO; GO:0045109; P:intermediate filament organization; ISO:RGD. DR GO; GO:0001822; P:kidney development; ISO:RGD. DR GO; GO:0060459; P:left lung development; ISO:RGD. DR GO; GO:0060174; P:limb bud formation; ISO:RGD. DR GO; GO:0060173; P:limb development; ISO:RGD. DR GO; GO:0097421; P:liver regeneration; IEP:RGD. DR GO; GO:0030324; P:lung development; ISS:UniProtKB. DR GO; GO:0060428; P:lung epithelium development; ISO:RGD. DR GO; GO:0060463; P:lung lobe morphogenesis; ISO:RGD. DR GO; GO:0060425; P:lung morphogenesis; ISO:RGD. DR GO; GO:0060484; P:lung-associated mesenchyme development; ISO:RGD. DR GO; GO:0002320; P:lymphoid progenitor cell differentiation; ISS:UniProtKB. DR GO; GO:0030539; P:male genitalia development; ISS:UniProtKB. DR GO; GO:0048808; P:male genitalia morphogenesis; IMP:RGD. DR GO; GO:0097152; P:mesenchymal cell apoptotic process; ISO:RGD. DR GO; GO:0010463; P:mesenchymal cell proliferation; ISO:RGD. DR GO; GO:0060916; P:mesenchymal cell proliferation involved in lung development; ISO:RGD. DR GO; GO:0060783; P:mesenchymal smoothened signaling pathway involved in prostate gland development; ISO:RGD. DR GO; GO:0072205; P:metanephric collecting duct development; ISO:RGD. DR GO; GO:0072136; P:metanephric mesenchymal cell proliferation involved in metanephros development; ISS:UniProtKB. DR GO; GO:0001656; P:metanephros development; ISS:UniProtKB. DR GO; GO:0030901; P:midbrain development; ISS:UniProtKB. DR GO; GO:0045445; P:myoblast differentiation; ISO:RGD. DR GO; GO:0014902; P:myotube differentiation; ISO:RGD. DR GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; ISO:RGD. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:RGD. DR GO; GO:0045596; P:negative regulation of cell differentiation; ISS:UniProtKB. DR GO; GO:0030336; P:negative regulation of cell migration; ISS:UniProtKB. DR GO; GO:0090370; P:negative regulation of cholesterol efflux; ISO:RGD. DR GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; ISO:RGD. DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD. DR GO; GO:2000357; P:negative regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB. DR GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; ISO:RGD. DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISO:RGD. DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:RGD. DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISO:RGD. DR GO; GO:0033085; P:negative regulation of T cell differentiation in thymus; ISO:RGD. DR GO; GO:0042130; P:negative regulation of T cell proliferation; ISO:RGD. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0034244; P:negative regulation of transcription elongation by RNA polymerase II; ISO:RGD. DR GO; GO:2000062; P:negative regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB. DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISO:RGD. DR GO; GO:0045060; P:negative thymic T cell selection; ISS:UniProtKB. DR GO; GO:0001755; P:neural crest cell migration; ISS:UniProtKB. DR GO; GO:0001841; P:neural tube formation; IMP:RGD. DR GO; GO:0007405; P:neuroblast proliferation; ISS:UniProtKB. DR GO; GO:0030182; P:neuron differentiation; ISO:RGD. DR GO; GO:0048663; P:neuron fate commitment; ISS:UniProtKB. DR GO; GO:0042476; P:odontogenesis; ISO:RGD. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; ISO:RGD. DR GO; GO:0014003; P:oligodendrocyte development; ISO:RGD. DR GO; GO:0048709; P:oligodendrocyte differentiation; ISO:RGD. DR GO; GO:0002076; P:osteoblast development; ISO:RGD. DR GO; GO:0031016; P:pancreas development; ISO:RGD. DR GO; GO:0007389; P:pattern specification process; ISS:UniProtKB. DR GO; GO:0009949; P:polarity specification of anterior/posterior axis; ISS:UniProtKB. DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; ISS:UniProtKB. DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; ISO:RGD. DR GO; GO:0051781; P:positive regulation of cell division; ISO:RGD. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:RGD. DR GO; GO:0021940; P:positive regulation of cerebellar granule cell precursor proliferation; ISO:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; IDA:RGD. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:RGD. DR GO; GO:0060769; P:positive regulation of epithelial cell proliferation involved in prostate gland development; ISO:RGD. DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD. DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; ISS:UniProtKB. DR GO; GO:2000358; P:positive regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB. DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; ISO:RGD. DR GO; GO:2000729; P:positive regulation of mesenchymal cell proliferation involved in ureter development; ISS:UniProtKB. DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IMP:RGD. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IMP:RGD. DR GO; GO:0032901; P:positive regulation of neurotrophin production; IMP:RGD. DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; ISO:RGD. DR GO; GO:0070447; P:positive regulation of oligodendrocyte progenitor proliferation; IDA:RGD. DR GO; GO:0060406; P:positive regulation of penile erection; IMP:RGD. DR GO; GO:0046534; P:positive regulation of photoreceptor cell differentiation; IDA:RGD. DR GO; GO:0042307; P:positive regulation of protein import into nucleus; ISO:RGD. DR GO; GO:0061189; P:positive regulation of sclerotome development; ISO:RGD. DR GO; GO:0014858; P:positive regulation of skeletal muscle cell proliferation; ISO:RGD. DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; ISO:RGD. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISS:UniProtKB. DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IDA:RGD. DR GO; GO:0051155; P:positive regulation of striated muscle cell differentiation; ISO:RGD. DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:2000063; P:positive regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB. DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; ISO:RGD. DR GO; GO:0045059; P:positive thymic T cell selection; ISS:UniProtKB. DR GO; GO:0060516; P:primary prostatic bud elongation; ISO:RGD. DR GO; GO:0060523; P:prostate epithelial cord elongation; ISO:RGD. DR GO; GO:0030850; P:prostate gland development; IEP:RGD. DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro. DR GO; GO:0006606; P:protein import into nucleus; ISO:RGD. DR GO; GO:0034504; P:protein localization to nucleus; ISO:RGD. DR GO; GO:0042127; P:regulation of cell population proliferation; IDA:RGD. DR GO; GO:0006355; P:regulation of DNA-templated transcription; ISO:RGD. DR GO; GO:0030856; P:regulation of epithelial cell differentiation; IEP:RGD. DR GO; GO:0060768; P:regulation of epithelial cell proliferation involved in prostate gland development; ISO:RGD. DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD. DR GO; GO:0060251; P:regulation of glial cell proliferation; ISO:RGD. DR GO; GO:0060782; P:regulation of mesenchymal cell proliferation involved in prostate gland development; ISO:RGD. DR GO; GO:0042481; P:regulation of odontogenesis; ISO:RGD. DR GO; GO:0060685; P:regulation of prostatic bud formation; ISO:RGD. DR GO; GO:1900180; P:regulation of protein localization to nucleus; ISO:RGD. DR GO; GO:0030162; P:regulation of proteolysis; ISS:UniProtKB. DR GO; GO:0072091; P:regulation of stem cell proliferation; ISO:RGD. DR GO; GO:0030323; P:respiratory tube development; ISO:RGD. DR GO; GO:0048678; P:response to axon injury; IMP:RGD. DR GO; GO:0032355; P:response to estradiol; IEP:RGD. DR GO; GO:0045471; P:response to ethanol; IDA:RGD. DR GO; GO:0001666; P:response to hypoxia; IEP:RGD. DR GO; GO:0010243; P:response to organonitrogen compound; IEP:RGD. DR GO; GO:0032526; P:response to retinoic acid; IEP:RGD. DR GO; GO:0060458; P:right lung development; ISO:RGD. DR GO; GO:0060021; P:roof of mouth development; ISO:RGD. DR GO; GO:0060662; P:salivary gland cavitation; ISO:RGD. DR GO; GO:0097264; P:self proteolysis; ISS:UniProtKB. DR GO; GO:0014856; P:skeletal muscle cell proliferation; ISO:RGD. DR GO; GO:0098528; P:skeletal muscle fiber differentiation; ISO:RGD. DR GO; GO:0007519; P:skeletal muscle tissue development; ISO:RGD. DR GO; GO:0043588; P:skin development; ISO:RGD. DR GO; GO:0048745; P:smooth muscle tissue development; ISO:RGD. DR GO; GO:0007224; P:smoothened signaling pathway; ISS:UniProtKB. DR GO; GO:0061053; P:somite development; ISO:RGD. DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IDA:MGI. DR GO; GO:0021522; P:spinal cord motor neuron differentiation; ISO:RGD. DR GO; GO:0048864; P:stem cell development; ISS:UniProtKB. DR GO; GO:0072089; P:stem cell proliferation; ISO:RGD. DR GO; GO:0051146; P:striated muscle cell differentiation; ISO:RGD. DR GO; GO:0014706; P:striated muscle tissue development; ISO:RGD. DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB. DR GO; GO:0042098; P:T cell proliferation; ISO:RGD. DR GO; GO:0021978; P:telencephalon regionalization; IMP:RGD. DR GO; GO:0021794; P:thalamus development; ISO:RGD. DR GO; GO:0048538; P:thymus development; ISS:UniProtKB. DR GO; GO:0030878; P:thyroid gland development; ISO:RGD. DR GO; GO:0043586; P:tongue development; IMP:RGD. DR GO; GO:0043587; P:tongue morphogenesis; IMP:RGD. DR GO; GO:0060438; P:trachea development; ISO:RGD. DR GO; GO:0060439; P:trachea morphogenesis; ISO:RGD. DR GO; GO:1905327; P:tracheoesophageal septum formation; ISO:RGD. DR GO; GO:0036484; P:trunk neural crest cell migration; ISO:RGD. DR GO; GO:0001944; P:vasculature development; ISO:RGD. DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB. DR GO; GO:0021521; P:ventral spinal cord interneuron specification; IDA:MGI. DR GO; GO:0022006; P:zona limitans intrathalamica formation; IDA:RGD. 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 InterPro; IPR006141; Intein_N. DR PANTHER; PTHR11889; HEDGEHOG; 1. DR PANTHER; PTHR11889:SF36; SONIC 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. DR PROSITE; PS50817; INTEIN_N_TER; 1. PE 1: Evidence at protein level; KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein; KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Hydrolase; KW Lipoprotein; Membrane; Metal-binding; Palmitate; Protease; KW Reference proteome; Signal; Transferase; Zinc. FT SIGNAL 1..24 FT /evidence="ECO:0000250|UniProtKB:Q15465" FT CHAIN 25..437 FT /note="Sonic hedgehog protein" FT /id="PRO_0000013214" FT CHAIN 25..198 FT /note="Sonic hedgehog protein N-product" FT /id="PRO_0000013215" FT MOTIF 33..39 FT /note="Cardin-Weintraub" FT /evidence="ECO:0000250|UniProtKB:Q62226" FT BINDING 90 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 91 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 91 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 96 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 126 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 127 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 127 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 130 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 132 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 141 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 148 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 183 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT SITE 198..199 FT /note="Cleavage; by autolysis" 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 25 FT /note="N-palmitoyl cysteine" FT /evidence="ECO:0000250" FT LIPID 198 FT /note="Cholesterol glycine ester" FT /evidence="ECO:0000250|UniProtKB:Q62226" FT CARBOHYD 279 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" SQ SEQUENCE 437 AA; 47630 MW; 0DBFC19F0D1662A0 CRC64; MLLLLARCFL VALASSLLVC PGLACGPGRG FGKRQHPKKL TPLAYKQFIP NVAEKTLGAS GRYEGKITRN SERFKELTPN YNPDIIFKDE ENTGADRLMT QRCKDKLNAL AISVMNQWPG VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRSKYG MLARLAVEAG FDWVYYESKA RIHCSVKAEN SVAAKSDGCF PGSATVHLEQ GGTKLVKDLS PGDRVLAADD QGRLLYSDFL TFLDRDEGAK KVFYVIETRE PRERLLLTAA HLLFVAPHND SGPTPGPSPL FASRVRPGQR VYVVAERGGD RRLLPAAVHS VTLREEAAGA YAPLTADGTI LINRVLASCY AVIEEHSWAH RAFAPFRLAH ALLAALAPAR TDGGGGGSIP APQSVAEARG AGPPAGIHWY SQLLYHIGTW LLDSETLHPL GMAVKSS //