ID SHH_CYNPY Reviewed; 432 AA. AC Q90385; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 22-FEB-2023, entry version 116. DE RecName: Full=Sonic hedgehog protein {ECO:0000305}; DE Short=SHH; DE EC=3.1.-.- {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:0000250|UniProtKB:Q15465}; OS Cynops pyrrhogaster (Japanese fire-bellied newt) (Molge pyrrhogaster). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Amphibia; OC Batrachia; Caudata; Salamandroidea; Salamandridae; Pleurodelinae; Cynops. OX NCBI_TaxID=8330; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION. RC TISSUE=Embryo; RX PubMed=8573168; DOI=10.1006/bbrc.1996.0069; RA Takabatake T., Takahashi T.C., Inoue K., Ogawa M., Takeshima K.; RT "Activation of two Cynops genes, fork head and sonic hedgehog, in animal RT cap explants."; RL Biochem. Biophys. Res. Commun. 218:395-401(1996). 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}. CC -!- CATALYTIC ACTIVITY: 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). CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}. 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 -!- INDUCTION: Activated by activin, basic fibroblast growth factor (BFGF) CC and fork head. {ECO:0000269|PubMed:8573168}. 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; D63339; BAA09657.1; -; mRNA. DR AlphaFoldDB; Q90385; -. DR SMR; Q90385; -. DR MEROPS; C46.002; -. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0140853; F:cholesterol-protein transferase activity; ISS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro. DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISS:UniProtKB. DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro. DR GO; GO:0097264; P:self proteolysis; ISS:UniProtKB. DR GO; GO:0048731; P:system development; IEA:UniProt. 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 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; Signal; Transferase; Zinc. FT SIGNAL 1..26 FT /evidence="ECO:0000255" FT CHAIN 27..432 FT /note="Sonic hedgehog protein" FT /id="PRO_0000013223" FT CHAIN 27..200 FT /note="Sonic hedgehog protein N-product" FT /id="PRO_0000013224" FT MOTIF 35..41 FT /note="Cardin-Weintraub" FT /evidence="ECO:0000250|UniProtKB:Q62226" FT BINDING 92 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 93 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 93 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 98 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 128 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 129 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 129 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 134 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 143 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 150 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 185 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT SITE 200..201 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 246 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 27 FT /note="N-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT LIPID 200 FT /note="Cholesterol glycine ester" FT /evidence="ECO:0000250|UniProtKB:Q62226" SQ SEQUENCE 432 AA; 47847 MW; B455C7E746C8E5A8 CRC64; MDEMILLRRV LLAGFICALL VPSGLSCGPG RGIGTRKRFK KLTPLAYKQF TPNVPEKTLG ASGRYEGKIT RNSERFKELT PNYNPDIIFK DEENTGADRL MTQRCKDKLN ALAISVMNQW PGVKLRVTEG WDEDGHHFEE SLHYEGRAVD ITTSDRDRSK YGMLARLAAE AGFDWVYFES KAHIHCSVKA ENSVAAKSGG CFPGSATVAL EQGVRIPVKD LRPGDRVLAA DGLGKLVYSD FLLFMDKEET VRKVFYVIET SRERVRLTAA HLLFVGQAHP GNDSGGDFRS VFGSAGFRSM FASSVRAGHR VLTVDREGRG LREATVERVY LEEATGAYAP VTAHGTVVID RVLASCYAVI EEHSWAHWAF APLRVGLGIL SFFSPQDYSS HSPPAPSQSE GVHWYSEILY RIGTWVLQED TIHPLGMAAK SS //