ID HH_DROME Reviewed; 471 AA. AC Q02936; A4V396; Q9VCQ4; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 01-SEP-2009, sequence version 4. DT 27-MAR-2024, entry version 234. DE RecName: Full=Protein hedgehog {ECO:0000305}; DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226}; DE Contains: DE RecName: Full=Protein hedgehog N-product; DE Short=Hh-Np; DE Short=N-Hh; DE Flags: Precursor; GN Name=hh {ECO:0000312|FlyBase:FBgn0004644}; GN ORFNames=CG4637 {ECO:0000312|FlyBase:FBgn0004644}; OS Drosophila melanogaster (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7227; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM LONG), FUNCTION, RP DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY. RC STRAIN=Canton-S; TISSUE=Embryo; RX PubMed=8166882; DOI=10.1016/0378-1119(93)90392-g; RA Tashiro S., Michiue T., Higashijima S., Zenno S., Ishimaru S., RA Takahashi F., Orihara M., Kojima T., Saigo K.; RT "Structure and expression of hedgehog, a Drosophila segment-polarity gene RT required for cell-cell communication."; RL Gene 124:183-189(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DEVELOPMENTAL STAGE, AND RP TISSUE SPECIFICITY. RX PubMed=1394430; DOI=10.1016/0092-8674(92)90264-d; RA Lee J.J., von Kessler D.P., Parks S., Beachy P.A.; RT "Secretion and localized transcription suggest a role in positional RT signaling for products of the segmentation gene hedgehog."; RL Cell 71:33-50(1992). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, SUBCELLULAR RP LOCATION, DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY. RC STRAIN=Oregon-R; TISSUE=Embryo; RX PubMed=1280560; DOI=10.1242/dev.115.4.957; RA Mohler J., Vani K.; RT "Molecular organization and embryonic expression of the hedgehog gene RT involved in cell-cell communication in segmental patterning of RT Drosophila."; RL Development 115:957-971(1992). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), FUNCTION, DEVELOPMENTAL STAGE, RP AND TISSUE SPECIFICITY. RC STRAIN=Oregon-R; TISSUE=Embryo; RX PubMed=1340474; DOI=10.1101/gad.6.12b.2635; RA Tabata T., Eaton S., Kornberg T.B.; RT "The Drosophila hedgehog gene is expressed specifically in posterior RT compartment cells and is a target of engrailed regulation."; RL Genes Dev. 6:2635-2645(1992). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Berkeley; RX PubMed=10731132; DOI=10.1126/science.287.5461.2185; RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C., RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D., RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R., RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., RA Venter J.C.; RT "The genome sequence of Drosophila melanogaster."; RL Science 287:2185-2195(2000). RN [6] RP GENOME REANNOTATION. RC STRAIN=Berkeley; RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083; RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A., RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M., RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic RT review."; RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002). RN [7] RP AUTOCATALYTIC CLEAVAGE, AND PROTEOLYTIC PROCESSING. RX PubMed=7885476; DOI=10.1038/374363a0; RA Porter J.A., von Kessler D.P., Ekker S.C., Young K.E., Lee J.J., Moses K., RA Beachy P.A.; RT "The product of hedgehog autoproteolytic cleavage active in local and long- RT range signalling."; RL Nature 374:363-366(1995). RN [8] RP FUNCTION, AND MUTAGENESIS OF CYS-85. RX PubMed=11319862; DOI=10.1006/dbio.2001.0218; RA Lee J.D., Kraus P., Gaiano N., Nery S., Kohtz J., Fishell G., Loomis C.A., RA Treisman J.E.; RT "An acylatable residue of Hedgehog is differentially required in Drosophila RT and mouse limb development."; RL Dev. Biol. 233:122-136(2001). RN [9] RP PALMITOYLATION AT CYS-85, CHOLESTERYLATION AT GLY-257, MUTAGENESIS OF RP CYS-85, AND MASS SPECTROMETRY. RX PubMed=11486055; DOI=10.1126/science.1064437; RA Chamoun Z., Mann R.K., Nellen D., von Kessler D.P., Bellotto M., RA Beachy P.A., Basler K.; RT "Skinny hedgehog, an acyltransferase required for palmitoylation and RT activity of the hedgehog signal."; RL Science 293:2080-2084(2001). RN [10] RP ROLE OF CHOLESTEROL, AND SUBCELLULAR LOCATION. RX PubMed=12586063; DOI=10.1016/s1534-5807(03)00031-5; RA Gallet A., Rodriguez R., Ruel L., Therond P.P.; RT "Cholesterol modification of hedgehog is required for trafficking and RT movement, revealing an asymmetric cellular response to hedgehog."; RL Dev. Cell 4:191-204(2003). RN [11] RP INTERACTION WITH SHF. RX PubMed=15691765; DOI=10.1016/j.devcel.2004.12.018; RA Gorfinkiel N., Sierra J., Callejo A., Ibanez C., Guerrero I.; RT "The Drosophila ortholog of the human wnt inhibitor factor shifted controls RT the diffusion of lipid-modified hedgehog."; RL Dev. Cell 8:241-253(2005). RN [12] RP ROLE OF LIPOPHORIN IN MOVEMENT. RX PubMed=15875013; DOI=10.1038/nature03504; RA Panakova D., Sprong H., Marois E., Thiele C., Eaton S.; RT "Lipoprotein particles are required for Hedgehog and Wingless signalling."; RL Nature 435:58-65(2005). RN [13] RP FUNCTION, TISSUE SPECIFICITY, INDUCTION BY BACTERIAL URACIL, AND DISRUPTION RP PHENOTYPE. RX PubMed=25639794; DOI=10.1016/j.chom.2014.12.012; RA Lee K.A., Kim B., Bhin J., Kim D.H., You H., Kim E.K., Kim S.H., Ryu J.H., RA Hwang D., Lee W.J.; RT "Bacterial uracil modulates Drosophila DUOX-dependent gut immunity via RT Hedgehog-induced signaling endosomes."; RL Cell Host Microbe 17:191-204(2015). RN [14] RP FUNCTION. RX PubMed=27195754; DOI=10.1371/journal.pgen.1006054; RA Li T., Fan J., Blanco-Sanchez B., Giagtzoglou N., Lin G., Yamamoto S., RA Jaiswal M., Chen K., Zhang J., Wei W., Lewis M.T., Groves A.K., RA Westerfield M., Jia J., Bellen H.J.; RT "Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal- RT 2 and Kif7 through Poly-ubiquitination."; RL PLoS Genet. 12:E1006054-E1006054(2016). RN [15] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 258-402, AND MUTAGENESIS OF RP ASP-303; THR-326 AND HIS-329. RX PubMed=9335337; DOI=10.1016/s0092-8674(01)80011-8; RA Hall T.M.T., Porter J.A., Young K.E., Koonin E.V., Beachy P.A., Leahy D.J.; RT "Crystal structure of a Hedgehog autoprocessing domain: homology between RT Hedgehog and self-splicing proteins."; RL Cell 91:85-97(1997). 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) (PubMed:7885476). In addition, the C-terminal part displays CC a 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 (PubMed:12586063). CC {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:12586063, CC ECO:0000269|PubMed:7885476}. 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 (PubMed:25639794, PubMed:27195754, CC PubMed:8166882, PubMed:1394430, PubMed:1340474, PubMed:11319862). CC Establishes the anterior-posterior axis of the embryonic segments and CC patterns the larval imaginal disks. Binds to the patched (ptc) CC receptor, which functions in association with smoothened (smo), to CC activate the transcription of target genes wingless (wg), CC decapentaplegic (dpp) and ptc. In the absence of hh, ptc represses the CC constitutive signaling activity of smo through fused (fu). Essential CC component of a signaling pathway which regulates the Duox-dependent gut CC immune response to bacterial uracil; required to activate Cad99C- CC dependent endosome formation, norpA-dependent Ca2+ mobilization and p38 CC MAPK, which are essential steps in the Duox-dependent production of CC reactive oxygen species (ROS) in response to intestinal bacterial CC infection (PubMed:25639794). During photoreceptor differentiation, it CC up-regulates transcription of Ubr3, which in turn promotes the hh- CC signaling pathway by mediating the ubiquitination and degradation of CC cos (PubMed:27195754, PubMed:25639794, PubMed:8166882, PubMed:1394430, CC PubMed:1340474, PubMed:11319862). {ECO:0000269|PubMed:11319862, CC ECO:0000269|PubMed:1340474, ECO:0000269|PubMed:1394430, CC ECO:0000269|PubMed:25639794, ECO:0000269|PubMed:27195754, CC ECO:0000269|PubMed:8166882}. 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:0000269|PubMed:15691765}. CC -!- INTERACTION: CC Q02936-1; Q9VM64: ihog; NbExp=6; IntAct=EBI-15609026, EBI-94134; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:1280560}. Cytoplasm CC {ECO:0000269|PubMed:1280560}. Note=Nuclear up to embryonic stage 10 and CC then at stage 11 shifts to the cytoplasm (PubMed:1280560). Also CC secreted in either cleaved or uncleaved form to mediate signaling to CC other cells (PubMed:1280560). CC -!- SUBCELLULAR LOCATION: [Protein hedgehog N-product]: Cell membrane CC {ECO:0000269|PubMed:12586063}; Lipid-anchor CC {ECO:0000269|PubMed:12586063}. Note=The N-terminal peptide remains CC associated with the cell surface (PubMed:12586063). Heparan sulfate CC proteoglycans of the extracellular matrix play an essential role in CC diffusion. Lipophorin is required for diffusion, probably by acting as CC vehicle for its movement, explaining how it can spread over long CC distances despite its lipidation (PubMed:15875013). CC {ECO:0000269|PubMed:15875013}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; Synonyms=A, B; CC IsoId=Q02936-1; Sequence=Displayed; CC Name=Short; CC IsoId=Q02936-2; Sequence=VSP_002065, VSP_002066; CC -!- TISSUE SPECIFICITY: In embryos, expression starts at stage 5 as a few CC stripes at the anterior and posterior ends, this expands to 17 stripes CC during stages 8-11 (PubMed:8166882, PubMed:1280560, PubMed:1340474). CC Expression is also seen in CNS and some PNS cells until stage 13-14, CC and in foregut, hindgut and salivary glands (PubMed:1340474). In CC larvae, expression is seen in the posterior compartment of the wing, CC leg and antennal imaginal disks (PubMed:1394430, PubMed:1340474). In CC adults, high level of expression in specific regions of the CC proventriculus and hindgut, with slightly lower levels of expression in CC the posterior midgut (PubMed:25639794). Relatively low levels of CC expression in the anterior midgut region (PubMed:25639794). CC {ECO:0000269|PubMed:1280560, ECO:0000269|PubMed:1340474, CC ECO:0000269|PubMed:1394430, ECO:0000269|PubMed:25639794, CC ECO:0000269|PubMed:8166882}. CC -!- DEVELOPMENTAL STAGE: Expressed in embryos, larvae and pupae at high CC levels with maximum expression in 6-12 hours embryos and 0-24 hours CC pupae (PubMed:8166882, PubMed:1394430, PubMed:1280560, PubMed:1340474). CC Low levels of expression are seen in adults (PubMed:8166882, CC PubMed:1394430). {ECO:0000269|PubMed:1280560, CC ECO:0000269|PubMed:1340474, ECO:0000269|PubMed:1394430, CC ECO:0000269|PubMed:8166882}. CC -!- INDUCTION: Strongly up-regulated in the anterior midgut and the CC posterior midgut in response to bacterial uracil. CC {ECO:0000269|PubMed:25639794}. 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) (PubMed:7885476). 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:Q15465, ECO:0000250|UniProtKB:Q62226, CC ECO:0000269|PubMed:7885476}. 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:0000269|PubMed:11486055}. CC -!- MASS SPECTROMETRY: [Protein hedgehog N-product]: Mass=20238.44; CC Method=MALDI; Evidence={ECO:0000269|PubMed:11486055}; CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown severely reduces adult CC survival following the ingestion of E.carotovora. Abolishes Cad99C- CC dependent formation of endosomes and DUOX-dependent up-regulation of CC reactive oxygen species (ROS) in the intestines of adults fed bacteria- CC derived uracil. {ECO:0000269|PubMed:25639794}. CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA28604.1; Type=Frameshift; Evidence={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; L05404; AAA28604.1; ALT_FRAME; mRNA. DR EMBL; L05405; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; L02793; AAA16458.1; -; Unassigned_DNA. DR EMBL; Z11840; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; S66384; AAB28646.1; -; mRNA. DR EMBL; AE014297; AAF56102.1; -; Genomic_DNA. DR EMBL; AE014297; ABC66186.1; -; Genomic_DNA. DR PIR; A46400; A46400. DR RefSeq; NP_001034065.1; NM_001038976.1. [Q02936-1] DR PDB; 1AT0; X-ray; 1.90 A; A=258-402. DR PDB; 2IBG; X-ray; 2.20 A; E/F/G/H=99-248. DR PDB; 6TD6; EM; 4.76 A; B=1-471. DR PDB; 6TYY; X-ray; 1.36 A; A=258-403. DR PDBsum; 1AT0; -. DR PDBsum; 2IBG; -. DR PDBsum; 6TD6; -. DR PDBsum; 6TYY; -. DR AlphaFoldDB; Q02936; -. DR BMRB; Q02936; -. DR EMDB; EMD-10464; -. DR SMR; Q02936; -. DR BioGRID; 67682; 79. DR DIP; DIP-51313N; -. DR IntAct; Q02936; 3. DR STRING; 7227.FBpp0099945; -. DR MEROPS; C46.001; -. DR PaxDb; 7227-FBpp0099945; -. DR EnsemblMetazoa; FBtr0100506; FBpp0099945; FBgn0004644. [Q02936-1] DR GeneID; 42737; -. DR KEGG; dme:Dmel_CG4637; -. DR UCSC; CG4637-RA; d. melanogaster. [Q02936-1] DR UCSC; CG4637-RB; d. melanogaster. DR AGR; FB:FBgn0004644; -. DR CTD; 42737; -. DR FlyBase; FBgn0004644; hh. DR VEuPathDB; VectorBase:FBgn0004644; -. DR eggNOG; KOG3638; Eukaryota. DR GeneTree; ENSGT00940000161132; -. DR HOGENOM; CLU_034686_0_0_1; -. DR InParanoid; Q02936; -. DR OMA; GSHKLFY; -. DR OrthoDB; 197397at2759; -. DR PhylomeDB; Q02936; -. DR Reactome; R-DME-209338; Assembly of the 'signalling complexes'. DR Reactome; R-DME-209471; Formation and transport of the N-HH ligand. DR Reactome; R-DME-5358346; Hedgehog ligand biogenesis. DR Reactome; R-DME-5362798; Release of Hh-Np from the secreting cell. DR Reactome; R-DME-5632681; Ligand-receptor interactions. DR SignaLink; Q02936; -. DR BioGRID-ORCS; 42737; 0 hits in 3 CRISPR screens. DR EvolutionaryTrace; Q02936; -. DR GenomeRNAi; 42737; -. DR PRO; PR:Q02936; -. DR Proteomes; UP000000803; Chromosome 3R. DR Bgee; FBgn0004644; Expressed in endoderm anlage (Drosophila) and 48 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:FlyBase. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030139; C:endocytic vesicle; IDA:FlyBase. DR GO; GO:0005768; C:endosome; IDA:FlyBase. DR GO; GO:0005576; C:extracellular region; IDA:FlyBase. DR GO; GO:0005615; C:extracellular space; IDA:FlyBase. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:FlyBase. 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:0016015; F:morphogen activity; IDA:FlyBase. DR GO; GO:0005113; F:patched binding; IPI:FlyBase. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0007487; P:analia development; TAS:FlyBase. DR GO; GO:0035288; P:anterior head segmentation; TAS:FlyBase. DR GO; GO:0048099; P:anterior/posterior lineage restriction, imaginal disc; TAS:FlyBase. DR GO; GO:0001746; P:Bolwig's organ morphogenesis; IMP:FlyBase. DR GO; GO:0001708; P:cell fate specification; IBA:GO_Central. DR GO; GO:0045168; P:cell-cell signaling involved in cell fate commitment; IMP:UniProtKB. DR GO; GO:0007386; P:compartment pattern specification; TAS:FlyBase. DR GO; GO:0001745; P:compound eye morphogenesis; IMP:FlyBase. DR GO; GO:0001751; P:compound eye photoreceptor cell differentiation; TAS:FlyBase. DR GO; GO:0035231; P:cytoneme assembly; IMP:FlyBase. DR GO; GO:0048066; P:developmental pigmentation; TAS:FlyBase. DR GO; GO:0009880; P:embryonic pattern specification; IEP:UniProtKB. DR GO; GO:0008544; P:epidermis development; TAS:FlyBase. DR GO; GO:0007427; P:epithelial cell migration, open tracheal system; IMP:FlyBase. DR GO; GO:0007440; P:foregut morphogenesis; TAS:FlyBase. DR GO; GO:0035224; P:genital disc anterior/posterior pattern formation; IEP:FlyBase. DR GO; GO:0035215; P:genital disc development; IMP:FlyBase. DR GO; GO:0035232; P:germ cell attraction; TAS:FlyBase. DR GO; GO:0008354; P:germ cell migration; IMP:FlyBase. DR GO; GO:0008347; P:glial cell migration; IMP:FlyBase. DR GO; GO:0007506; P:gonadal mesoderm development; IMP:FlyBase. DR GO; GO:0007507; P:heart development; TAS:FlyBase. DR GO; GO:0060914; P:heart formation; IMP:FlyBase. DR GO; GO:0007442; P:hindgut morphogenesis; IMP:FlyBase. DR GO; GO:0007446; P:imaginal disc growth; TAS:FlyBase. DR GO; GO:0007476; P:imaginal disc-derived wing morphogenesis; IMP:FlyBase. DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro. DR GO; GO:0035217; P:labial disc development; IMP:FlyBase. DR GO; GO:0007478; P:leg disc morphogenesis; TAS:FlyBase. DR GO; GO:0016335; P:morphogenesis of larval imaginal disc epithelium; IMP:FlyBase. DR GO; GO:0002385; P:mucosal immune response; IMP:FlyBase. DR GO; GO:0034111; P:negative regulation of homotypic cell-cell adhesion; IDA:FlyBase. DR GO; GO:0045861; P:negative regulation of proteolysis; IDA:FlyBase. DR GO; GO:0007280; P:pole cell migration; IGI:FlyBase. DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IMP:FlyBase. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IDA:FlyBase. DR GO; GO:0035289; P:posterior head segmentation; TAS:FlyBase. DR GO; GO:0007458; P:progression of morphogenetic furrow involved in compound eye morphogenesis; IMP:FlyBase. DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB. DR GO; GO:2000495; P:regulation of cell proliferation involved in compound eye morphogenesis; IMP:FlyBase. DR GO; GO:2000274; P:regulation of epithelial cell migration, open tracheal system; IMP:FlyBase. DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central. DR GO; GO:0007346; P:regulation of mitotic cell cycle; IMP:FlyBase. DR GO; GO:0007367; P:segment polarity determination; IMP:FlyBase. DR GO; GO:0097264; P:self proteolysis; ISS:UniProtKB. DR GO; GO:0007224; P:smoothened signaling pathway; IDA:FlyBase. DR GO; GO:0035277; P:spiracle morphogenesis, open tracheal system; IMP:FlyBase. DR GO; GO:0035154; P:terminal cell fate specification, open tracheal system; IMP:FlyBase. DR GO; GO:0035290; P:trunk segmentation; TAS:FlyBase. DR GO; GO:0007418; P:ventral midline development; IMP:FlyBase. DR GO; GO:0048100; P:wing disc anterior/posterior pattern formation; TAS:FlyBase. DR GO; GO:0035222; P:wing disc pattern formation; IDA:FlyBase. DR GO; GO:0007473; P:wing disc proximal/distal pattern formation; TAS:FlyBase. 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. DR Genevisible; Q02936; DM. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autocatalytic cleavage; Calcium; KW Cell membrane; Cytoplasm; Developmental protein; Hydrolase; Lipoprotein; KW Membrane; Metal-binding; Morphogen; Nucleus; Palmitate; Protease; KW Reference proteome; Segmentation polarity protein; Signal; Transferase. FT SIGNAL 1..? FT /evidence="ECO:0000255" FT PROPEP ?..84 FT /evidence="ECO:0000255" FT /id="PRO_0000383048" FT CHAIN 85..471 FT /note="Protein hedgehog" FT /id="PRO_0000013202" FT CHAIN 85..257 FT /note="Protein hedgehog N-product" FT /id="PRO_0000013203" 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 150 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 150 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 155 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 185 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 186 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 186 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 189 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT BINDING 191 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q15465" FT SITE 257..258 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:7885476" FT SITE 303 FT /note="Involved in cholesterol transfer" FT /evidence="ECO:0000269|PubMed:9335337" FT SITE 326 FT /note="Involved in auto-cleavage" FT /evidence="ECO:0000269|PubMed:9335337" FT SITE 329 FT /note="Essential for auto-cleavage" FT /evidence="ECO:0000269|PubMed:7885476, FT ECO:0000269|PubMed:9335337" FT LIPID 85 FT /note="N-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:11486055" FT LIPID 257 FT /note="Cholesterol glycine ester" FT /evidence="ECO:0000269|PubMed:11486055" FT VAR_SEQ 161..192 FT /note="RCKEKLNVLAYSVMNEWPGIRLLVTESWDEDY -> VRKTLKHRKLVTKFVI FT HHWESFAYRNHCDKVT (in isoform Short)" FT /evidence="ECO:0000305" FT /id="VSP_002065" FT VAR_SEQ 193..471 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000305" FT /id="VSP_002066" FT MUTAGEN 85 FT /note="C->S: N-product is made but fails to undergo FT palmitoylation." FT /evidence="ECO:0000269|PubMed:11319862, FT ECO:0000269|PubMed:11486055" FT MUTAGEN 303 FT /note="D->A: No cholesterol transfer." FT /evidence="ECO:0000269|PubMed:9335337" FT MUTAGEN 326 FT /note="T->A: Greatly reduced autoprocessing activity." FT /evidence="ECO:0000269|PubMed:9335337" FT MUTAGEN 329 FT /note="H->A: No autoprocessing activity." FT /evidence="ECO:0000269|PubMed:9335337" FT CONFLICT 156 FT /note="R -> G (in Ref. 1; AAA28604)" FT /evidence="ECO:0000305" FT CONFLICT 347 FT /note="D -> H (in Ref. 1; AAA28604)" FT /evidence="ECO:0000305" FT CONFLICT 373 FT /note="V -> L (in Ref. 1; AAA28604)" FT /evidence="ECO:0000305" FT CONFLICT 407 FT /note="Q -> P (in Ref. 3; Z11840)" FT /evidence="ECO:0000305" FT STRAND 107..111 FT /evidence="ECO:0007829|PDB:2IBG" FT TURN 116..119 FT /evidence="ECO:0007829|PDB:2IBG" FT HELIX 131..135 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:2IBG" FT HELIX 160..176 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 182..188 FT /evidence="ECO:0007829|PDB:2IBG" FT HELIX 199..202 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 205..210 FT /evidence="ECO:0007829|PDB:2IBG" FT HELIX 215..217 FT /evidence="ECO:0007829|PDB:2IBG" FT HELIX 218..228 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 231..234 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 241..244 FT /evidence="ECO:0007829|PDB:2IBG" FT STRAND 264..267 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 272..274 FT /evidence="ECO:0007829|PDB:6TYY" FT TURN 275..277 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 283..287 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 293..317 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 322..325 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 329..335 FT /evidence="ECO:0007829|PDB:6TYY" FT TURN 336..339 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 340..345 FT /evidence="ECO:0007829|PDB:6TYY" FT HELIX 346..348 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 354..358 FT /evidence="ECO:0007829|PDB:6TYY" FT TURN 360..362 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 365..393 FT /evidence="ECO:0007829|PDB:6TYY" FT STRAND 396..402 FT /evidence="ECO:0007829|PDB:6TYY" SQ SEQUENCE 471 AA; 52150 MW; 8ECD796A92FE7043 CRC64; MDNHSSVPWA SAASVTCLSL DAKCHSSSSS SSSKSAASSI SAIPQEETQT MRHIAHTQRC LSRLTSLVAL LLIVLPMVFS PAHSCGPGRG LGRHRARNLY PLVLKQTIPN LSEYTNSASG PLEGVIRRDS PKFKDLVPNY NRDILFRDEE GTGADRLMSK RCKEKLNVLA YSVMNEWPGI RLLVTESWDE DYHHGQESLH YEGRAVTIAT SDRDQSKYGM LARLAVEAGF DWVSYVSRRH IYCSVKSDSS ISSHVHGCFT PESTALLESG VRKPLGELSI GDRVLSMTAN GQAVYSEVIL FMDRNLEQMQ NFVQLHTDGG AVLTVTPAHL VSVWQPESQK LTFVFADRIE EKNQVLVRDV ETGELRPQRV VKVGSVRSKG VVAPLTREGT IVVNSVAASC YAVINSQSLA HWGLAPMRLL STLEAWLPAK EQLHSSPKVV SSAQQQNGIH WYANALYKVK DYVLPQSWRH D //