ID HH_DROER Reviewed; 465 AA. AC B3P7F8; DT 01-SEP-2009, integrated into UniProtKB/Swiss-Prot. DT 02-SEP-2008, sequence version 1. DT 22-FEB-2023, entry version 76. DE RecName: Full=Protein hedgehog {ECO:0000250|UniProtKB:Q02936}; DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226}; DE Contains: DE RecName: Full=Protein hedgehog N-product {ECO:0000250|UniProtKB:Q02936}; DE Flags: Precursor; GN Name=hh {ECO:0000250|UniProtKB:Q02936}; ORFNames=GG12458; OS Drosophila erecta (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7220; RN [1] {ECO:0000312|EMBL:EDV54047.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Tucson 14021-0224.01 {ECO:0000312|EMBL:EDV54047.1}; RX PubMed=17994087; DOI=10.1038/nature06341; RG Drosophila 12 genomes consortium; RT "Evolution of genes and genomes on the Drosophila phylogeny."; RL Nature 450:203-218(2007). CC -!- FUNCTION: [Protein hedgehog]: The C-terminal part of the hedgehog CC protein precursor displays an autoproteolysis activity that results in CC the cleavage of the full-length protein into two parts (N-product and CC C-product) (By similarity). In addition, the C-terminal part displays a CC cholesterol transferase activity that results by the covalent CC attachment of a cholesterol moiety to the C-terminal of the newly CC generated N-product (By similarity). Once cleaved, the C-product has no CC signaling activity and diffuses from the cell (By similarity). CC {ECO:0000250|UniProtKB:Q02936, ECO:0000250|UniProtKB:Q62226}. CC -!- FUNCTION: [Protein hedgehog N-product]: The dually lipidated hedgehog CC protein N-product is a morphogen which is essential for a variety of CC patterning events during development. Establishes the anterior- CC posterior axis of the embryonic segments and patterns the larval CC imaginal disks. Binds to the patched (ptc) receptor, which functions in CC association with smoothened (smo), to activate the transcription of CC target genes wingless (wg), decapentaplegic (dpp) and ptc. In the CC absence of hh, ptc represses the constitutive signaling activity of smo CC through fused (fu). Essential component of a signaling pathway which CC regulates the Duox-dependent gut immune response to bacterial uracil; CC required to activate Cad99C-dependent endosome formation, norpA- CC dependent Ca2+ mobilization and p38 MAPK, which are essential steps in CC the Duox-dependent production of reactive oxygen species (ROS) in CC response to intestinal bacterial infection. During photoreceptor CC differentiation, it up-regulates transcription of Ubr3, which in turn CC promotes the hh-signaling pathway by mediating the ubiquitination and CC degradation of cos. {ECO:0000250|UniProtKB:Q02936}. CC -!- CATALYTIC ACTIVITY: [Protein hedgehog]: 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 shf. {ECO:0000250|UniProtKB:Q02936}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q02936}. Cytoplasm CC {ECO:0000250|UniProtKB:Q02936}. Note=Nuclear up to embryonic stage 10 CC and then at stage 11 shifts to the cytoplasm. Also secreted in either CC cleaved or uncleaved form to mediate signaling to other cells. CC {ECO:0000250|UniProtKB:Q02936}. CC -!- SUBCELLULAR LOCATION: [Protein hedgehog N-product]: Cell membrane CC {ECO:0000250|UniProtKB:Q02936}; Lipid-anchor CC {ECO:0000250|UniProtKB:Q02936}. Note=The N-terminal peptide remains CC associated with the cell surface. Heparan sulfate proteoglycans of the CC extracellular matrix play an essential role in diffusion. Lipophorin is CC required for diffusion, probably by acting as vehicle for its movement, CC explaining how it can spread over long distances despite its CC lipidation. {ECO:0000250|UniProtKB:Q02936}. CC -!- PTM: [Protein hedgehog]: The C-terminal part of the hedgehog protein CC precursor displays an autoproteolysis activity that results in the CC cleavage of the full-length protein into two parts (N-product and C- CC product) (By similarity). In addition, the C-terminal part displays a CC cholesterol transferase activity that results by the covalent CC attachment of a cholesterol moiety to the C-terminal of the newly CC generated N-product (By similarity). The N-product is the active CC species in both local and long-range signaling, whereas the C-product CC has no signaling activity (By similarity). CC {ECO:0000250|UniProtKB:Q02936, ECO:0000250|UniProtKB:Q15465, CC ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Protein hedgehog N-product]: Cholesterylation is required for N- CC product targeting to lipid rafts and multimerization. CC {ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Protein hedgehog N-product]: N-palmitoylation by Rasp of the CC hedgehog N-product, within the secretory pathway, is required for the CC embryonic and larval patterning activities of the hedgehog signal. CC {ECO:0000250|UniProtKB:Q02936}. CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000255}. 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; CH954182; EDV54047.1; -; Genomic_DNA. DR RefSeq; XP_001982177.1; XM_001982141.2. DR AlphaFoldDB; B3P7F8; -. DR BMRB; B3P7F8; -. DR SMR; B3P7F8; -. DR STRING; 7220.FBpp0131004; -. DR MEROPS; C46.001; -. DR EnsemblMetazoa; FBtr0132512; FBpp0131004; FBgn0104746. DR GeneID; 6554619; -. DR KEGG; der:6554619; -. DR eggNOG; KOG3638; Eukaryota. DR HOGENOM; CLU_034686_0_0_1; -. DR OMA; APAVRGC; -. DR OrthoDB; 197397at2759; -. DR PhylomeDB; B3P7F8; -. DR Proteomes; UP000008711; Unassembled WGS sequence. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0030139; C:endocytic vesicle; IEA:EnsemblMetazoa. DR GO; GO:0005768; C:endosome; IEA:EnsemblMetazoa. DR GO; GO:0005615; C:extracellular space; IEA:EnsemblMetazoa. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. 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:0016015; F:morphogen activity; IEA:UniProtKB-KW. DR GO; GO:0005113; F:patched binding; IEA:EnsemblMetazoa. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0001746; P:Bolwig's organ morphogenesis; IEA:EnsemblMetazoa. DR GO; GO:0045168; P:cell-cell signaling involved in cell fate commitment; ISS:UniProtKB. DR GO; GO:0035231; P:cytoneme assembly; IEA:EnsemblMetazoa. DR GO; GO:0007427; P:epithelial cell migration, open tracheal system; IEA:EnsemblMetazoa. DR GO; GO:0035224; P:genital disc anterior/posterior pattern formation; IEA:EnsemblMetazoa. DR GO; GO:0008347; P:glial cell migration; IEA:EnsemblMetazoa. DR GO; GO:0007506; P:gonadal mesoderm development; IEA:EnsemblMetazoa. DR GO; GO:0060914; P:heart formation; IEA:EnsemblMetazoa. DR GO; GO:0007442; P:hindgut morphogenesis; IEA:EnsemblMetazoa. DR GO; GO:0007476; P:imaginal disc-derived wing morphogenesis; IEA:EnsemblMetazoa. DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro. DR GO; GO:0035217; P:labial disc development; IEA:EnsemblMetazoa. DR GO; GO:0016335; P:morphogenesis of larval imaginal disc epithelium; IEA:EnsemblMetazoa. DR GO; GO:0002385; P:mucosal immune response; IEA:EnsemblMetazoa. DR GO; GO:0034111; P:negative regulation of homotypic cell-cell adhesion; IEA:EnsemblMetazoa. DR GO; GO:0045861; P:negative regulation of proteolysis; IEA:EnsemblMetazoa. DR GO; GO:0007280; P:pole cell migration; IEA:EnsemblMetazoa. DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IEA:EnsemblMetazoa. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IEA:EnsemblMetazoa. DR GO; GO:0007458; P:progression of morphogenetic furrow involved in compound eye morphogenesis; IEA:EnsemblMetazoa. DR GO; GO:0016540; P:protein autoprocessing; IEA:EnsemblMetazoa. DR GO; GO:2000495; P:regulation of cell proliferation involved in compound eye morphogenesis; IEA:EnsemblMetazoa. DR GO; GO:2000274; P:regulation of epithelial cell migration, open tracheal system; IEA:EnsemblMetazoa. DR GO; GO:0007346; P:regulation of mitotic cell cycle; IEA:EnsemblMetazoa. DR GO; GO:0007367; P:segment polarity determination; ISS:UniProtKB. DR GO; GO:0097264; P:self proteolysis; ISS:UniProtKB. DR GO; GO:0007224; P:smoothened signaling pathway; IEA:EnsemblMetazoa. DR GO; GO:0035277; P:spiracle morphogenesis, open tracheal system; IEA:EnsemblMetazoa. DR GO; GO:0035154; P:terminal cell fate specification, open tracheal system; IEA:EnsemblMetazoa. DR GO; GO:0007418; P:ventral midline development; IEA:EnsemblMetazoa. DR GO; GO:0035222; P:wing disc pattern formation; IEA:EnsemblMetazoa. 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:SF31; PROTEIN HEDGEHOG; 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 3: Inferred from homology; KW Autocatalytic cleavage; Calcium; Cell membrane; Cytoplasm; KW Developmental protein; Hydrolase; Lipoprotein; Membrane; Metal-binding; KW Morphogen; Nucleus; Palmitate; Protease; Segmentation polarity protein; KW Signal; Transferase. FT SIGNAL 1..? FT /evidence="ECO:0000255" FT PROPEP ?..78 FT /evidence="ECO:0000255" FT /id="PRO_0000383054" FT CHAIN 79..465 FT /note="Protein hedgehog" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT /id="PRO_0000383055" FT CHAIN 79..251 FT /note="Protein hedgehog N-product" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT /id="PRO_0000383056" FT BINDING 143 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 144 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 144 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 149 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 179 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 180 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 180 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 183 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 185 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT SITE 251..252 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 297 FT /note="Involved in cholesterol transfer" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 320 FT /note="Involved in auto-cleavage" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 323 FT /note="Essential for auto-cleavage" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT LIPID 79 FT /note="N-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT LIPID 251 FT /note="Cholesterol glycine ester" FT /evidence="ECO:0000250|UniProtKB:Q02936" SQ SEQUENCE 465 AA; 51569 MW; DE0AEEFA4E52362D CRC64; MDNTSSVPWA SAASVTCLSL DAKCHSSSAK SAASSISASP ETQAMRHIAH TQRCLSRLTS LVALLLIVLP MTFSPAHSCG PGRGLGRHRA RNLYPLVLKQ TIPNLSEYTN SASGPLEGVI RRDSPKFKDL VPNYNRDILF RDEEGTGADR LMSKRCREKL NLLAYSVMNE WPGIRLLVTE SWDEDYHHGQ ESLHYEGRAV TIATSDRDQS KYGMLARLAV EAGFDWVSYV SRRHIYCSVK SDSSISSHVH GCFTPESTAL LENGVRKPLG ELSIGDRVLS MTANGQAVYS EVILFMDRNL EQMQNFVQLH TDGEAVLTVT PAHLVSVWQA ESQKLTFVFA DRVEEKNQVL VRDVETGELR PQRVVKVGSV RSKGVVAPLT REGTIVVNSV AASCYAVINS QSLAHWGLAP MRLLSTLEAW LPAKEQLHSS PKVVTTAEQQ NGIHWYANAL YKVKDYVLPQ SWRHD //