HH_DROPS
ID HH_DROPS Reviewed; 481 AA.
AC Q29AA9;
DT 01-SEP-2009, integrated into UniProtKB/Swiss-Prot.
DT 14-OCT-2008, sequence version 2.
DT 03-AUG-2022, entry version 94.
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-1; ORFNames=GA18321;
GN and
GN Name=hh-2; ORFNames=GA29124;
OS Drosophila pseudoobscura pseudoobscura (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=46245;
RN [1] {ECO:0000312|EMBL:EAL27441.2}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MV2-25 / Tucson 14011-0121.94;
RX PubMed=15632085; DOI=10.1101/gr.3059305;
RA Richards S., Liu Y., Bettencourt B.R., Hradecky P., Letovsky S.,
RA Nielsen R., Thornton K., Hubisz M.J., Chen R., Meisel R.P., Couronne O.,
RA Hua S., Smith M.A., Zhang P., Liu J., Bussemaker H.J., van Batenburg M.F.,
RA Howells S.L., Scherer S.E., Sodergren E., Matthews B.B., Crosby M.A.,
RA Schroeder A.J., Ortiz-Barrientos D., Rives C.M., Metzker M.L., Muzny D.M.,
RA Scott G., Steffen D., Wheeler D.A., Worley K.C., Havlak P., Durbin K.J.,
RA Egan A., Gill R., Hume J., Morgan M.B., Miner G., Hamilton C., Huang Y.,
RA Waldron L., Verduzco D., Clerc-Blankenburg K.P., Dubchak I., Noor M.A.F.,
RA Anderson W., White K.P., Clark A.G., Schaeffer S.W., Gelbart W.M.,
RA Weinstock G.M., Gibbs R.A.;
RT "Comparative genome sequencing of Drosophila pseudoobscura: chromosomal,
RT gene, and cis-element evolution.";
RL Genome Res. 15:1-18(2005).
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}.
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DR EMBL; CH676084; EDY71847.1; -; Genomic_DNA.
DR EMBL; CM000070; EAL27441.2; -; Genomic_DNA.
DR RefSeq; XP_001358303.2; XM_001358266.3.
DR RefSeq; XP_002136818.1; XM_002136782.2.
DR AlphaFoldDB; Q29AA9; -.
DR SMR; Q29AA9; -.
DR STRING; 7237.FBpp0282375; -.
DR MEROPS; C46.001; -.
DR EnsemblMetazoa; FBtr0283937; FBpp0282375; FBgn0078326.
DR EnsemblMetazoa; FBtr0289638; FBpp0288076; FBgn0250482.
DR GeneID; 4801169; -.
DR KEGG; dpo:Dpse_GA18321; -.
DR KEGG; dpo:Dpse_GA29124; -.
DR eggNOG; KOG3638; Eukaryota.
DR HOGENOM; CLU_034686_0_0_1; -.
DR InParanoid; Q29AA9; -.
DR OMA; APAVRGC; -.
DR Proteomes; UP000001819; Chromosome 2.
DR Bgee; FBgn0078326; Expressed in male reproductive system and 1 other tissue.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016015; F:morphogen activity; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IEA:UniProtKB-KW.
DR GO; GO:0045168; P:cell-cell signaling involved in cell fate commitment; ISS:UniProtKB.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0007367; P:segment polarity determination; ISS:UniProtKB.
DR GO; GO:0048731; P:system development; IEA:UniProt.
DR Gene3D; 3.30.1380.10; -; 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 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; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 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; Reference proteome;
KW Segmentation polarity protein; Signal.
FT SIGNAL 1..?
FT /evidence="ECO:0000255"
FT PROPEP ?..92
FT /evidence="ECO:0000255"
FT /id="PRO_0000383070"
FT CHAIN 93..481
FT /note="Protein hedgehog"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT /id="PRO_0000383071"
FT CHAIN 93..265
FT /note="Protein hedgehog N-product"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT /id="PRO_0000383072"
FT BINDING 157
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 158
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 158
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 163
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 193
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 194
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 194
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 197
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 199
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT SITE 265..266
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 311
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 334
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 337
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 93
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 265
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
SQ SEQUENCE 481 AA; 53485 MW; 1F21C76E2B87BE1C CRC64;
MDNHNEVPMS MSVPWASAAS VTCLSLDAKC HRPCPSSISA SASASACASD SAAIATTKLR
HIAYTQRCSS RLTMLMTVLL LLLPLSFTPA HSCGPGRGLG RRRERNLYPL VLKQTIPNLS
EYQTGASGPL EGEIKRDSPK FKDLVPNYNR DILFRDEEGT GADRLMTKRC KEKLNVLAYS
VMNEWPGVRL LVTESWDEDH QHGQESLHYE GRAVTIATSD REPSRYGMLA RLAVEAGFDW
VSYVSRRHIY CSVKSDSSIS SHVHGCFTPE STALLESGIT KPLSEISIGD RVLSMGSNGQ
PVYSEVILFM DRNLEQMQNF VELHTDGGAV LTVTPAHLIS VWHPERQQLD YVFADRVEEL
NYVLVRDPQT GELRPQRVVR VGSVRSKGVV APLTREGTIV VNSVAASCYA VIDSQSLAHW
GLAPMRILAM LQSWMPAKDQ LRSSQTEGVV SRAEQQNGIH WYANALYKVK DYVLPKSWRH
D
