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Database: UniProt
Entry: O43323
LinkDB: O43323
Original site: O43323 
ID   DHH_HUMAN               Reviewed;         396 AA.
AC   O43323; Q15794;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-1998, sequence version 1.
DT   02-JUN-2021, entry version 189.
DE   RecName: Full=Desert hedgehog protein;
DE            Short=DHH;
DE   AltName: Full=HHG-3;
DE   Contains:
DE     RecName: Full=Desert hedgehog protein N-product;
DE   Contains:
DE     RecName: Full=Desert hedgehog protein C-product;
DE   Flags: Precursor;
GN   Name=DHH;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Tate G., Kishimoto K., Mitsuya T.;
RT   "Expression of Sonic hedgehog and its receptor Patched/Smoothened in human
RT   cancer cell lines and embryonic organs.";
RL   J. Biochem. Mol. Biol. Biophys. 4:27-34(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 85-178.
RC   TISSUE=Kidney;
RA   Drummond I.A.;
RT   "Human desert hedgehog.";
RL   Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   INVOLVEMENT IN PGD.
RX   PubMed=11017805; DOI=10.1086/321210;
RA   Umehara F., Tate G., Itoh K., Yamaguchi N., Douchi T., Mitsuya T.,
RA   Osame M.;
RT   "A novel mutation of desert hedgehog in a patient with 46,XY partial
RT   gonadal dysgenesis accompanied by minifascicular neuropathy.";
RL   Am. J. Hum. Genet. 67:1302-1305(2000).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 39-194 IN COMPLEX WITH HHIP AND
RP   ZINC IONS, CALCIUM-BINDING, DOMAIN, AND INTERACTION WITH HHIP.
RX   PubMed=19561611; DOI=10.1038/nsmb.1607;
RA   Bishop B., Aricescu A.R., Harlos K., O'Callaghan C.A., Jones E.Y.,
RA   Siebold C.;
RT   "Structural insights into hedgehog ligand sequestration by the human
RT   hedgehog-interacting protein HHIP.";
RL   Nat. Struct. Mol. Biol. 16:698-703(2009).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 24-189 IN COMPLEXES WITH BOC;
RP   CDON; ZINC AND CALCIUM IONS, DOMAIN, AND INTERACTION WITH BOC AND CDON.
RX   PubMed=20519495; DOI=10.1074/jbc.m110.131680;
RA   Kavran J.M., Ward M.D., Oladosu O.O., Mulepati S., Leahy D.J.;
RT   "All mammalian Hedgehog proteins interact with cell adhesion molecule,
RT   down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved
RT   manner.";
RL   J. Biol. Chem. 285:24584-24590(2010).
RN   [7]
RP   VARIANT SRXY7 PRO-162.
RX   PubMed=15356051; DOI=10.1210/jc.2004-0863;
RA   Canto P., Soederlund D., Reyes E., Mendez J.P.;
RT   "Mutations in the desert hedgehog (DHH) gene in patients with 46,XY
RT   complete pure gonadal dysgenesis.";
RL   J. Clin. Endocrinol. Metab. 89:4480-4483(2004).
RN   [8]
RP   ERRATUM OF PUBMED:15356051.
RA   Canto P., Soederlund D., Reyes E., Mendez J.P.;
RL   J. Clin. Endocrinol. Metab. 89:5453-5453(2004).
CC   -!- FUNCTION: Intercellular signal essential for a variety of patterning
CC       events during development. May function as a spermatocyte survival
CC       factor in the testes. Essential for testes development.
CC   -!- SUBUNIT: Interacts with BOC and CDON. Interacts with HHIP.
CC       {ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495}.
CC   -!- INTERACTION:
CC       O43323; Q9BWV1: BOC; NbExp=2; IntAct=EBI-11667804, EBI-718555;
CC       O43323; Q4KMG0: CDON; NbExp=2; IntAct=EBI-11667804, EBI-7016840;
CC       O43323; Q96QV1-1: HHIP; NbExp=4; IntAct=EBI-11667804, EBI-15791478;
CC   -!- SUBCELLULAR LOCATION: [Desert hedgehog protein N-product]: Cell
CC       membrane {ECO:0000250}; Lipid-anchor {ECO:0000250}; Extracellular side
CC       {ECO:0000250}. Note=The N-terminal peptide remains associated with the
CC       cell surface. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: [Desert hedgehog protein C-product]: Secreted,
CC       extracellular space {ECO:0000250}. Note=The C-terminal peptide diffuses
CC       from the cell. {ECO:0000250}.
CC   -!- DOMAIN: The desert 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:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495}.
CC   -!- PTM: The C-terminal domain displays an autoproteolysis activity and a
CC       cholesterol transferase activity. Both activities result in the
CC       cleavage of the full-length protein and covalent attachment of a
CC       cholesterol moiety to the C-terminal of the newly generated N-terminal
CC       fragment (N-product). This covalent modification appears to play an
CC       essential role in restricting the spatial distribution of the protein
CC       activity to the cell surface. The N-product is the active species in
CC       both local and long-range signaling, whereas the C-product has no
CC       signaling activity (By similarity). {ECO:0000250}.
CC   -!- DISEASE: Partial gonadal dysgenesis with minifascicular neuropathy
CC       46,XY (PGD) [MIM:607080]: Characterized by the presence of a testis on
CC       one side and a streak or an absent gonad at the other, persistence of
CC       Muellerian duct structures, and a variable degree of genital ambiguity.
CC       {ECO:0000269|PubMed:11017805}. Note=The disease may be caused by
CC       variants affecting the gene represented in this entry.
CC   -!- DISEASE: 46,XY sex reversal 7 (SRXY7) [MIM:233420]: A disorder of sex
CC       development. Affected individuals have a 46,XY karyotype but present as
CC       phenotypically normal females. SRXY7 patients have no functional
CC       gonads. {ECO:0000269|PubMed:15356051}. Note=The disease may be caused
CC       by variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
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DR   EMBL; AB010994; BAA24866.1; -; Genomic_DNA.
DR   EMBL; BC033507; AAH33507.1; -; mRNA.
DR   EMBL; U59748; AAB03398.1; -; mRNA.
DR   CCDS; CCDS8779.1; -.
DR   PIR; G02735; G02735.
DR   RefSeq; NP_066382.1; NM_021044.3.
DR   PDB; 2WFQ; X-ray; 1.85 A; A=39-194.
DR   PDB; 2WFR; X-ray; 1.95 A; A=39-194.
DR   PDB; 2WG3; X-ray; 2.60 A; A/B=40-194.
DR   PDB; 3N1G; X-ray; 1.90 A; A/B=24-189.
DR   PDB; 3N1Q; X-ray; 2.89 A; A/B/E=24-189.
DR   PDBsum; 2WFQ; -.
DR   PDBsum; 2WFR; -.
DR   PDBsum; 2WG3; -.
DR   PDBsum; 3N1G; -.
DR   PDBsum; 3N1Q; -.
DR   SMR; O43323; -.
DR   BioGRID; 119151; 7.
DR   DIP; DIP-48538N; -.
DR   IntAct; O43323; 9.
DR   STRING; 9606.ENSP00000266991; -.
DR   MEROPS; C46.004; -.
DR   iPTMnet; O43323; -.
DR   PhosphoSitePlus; O43323; -.
DR   BioMuta; DHH; -.
DR   MassIVE; O43323; -.
DR   PaxDb; O43323; -.
DR   PeptideAtlas; O43323; -.
DR   PRIDE; O43323; -.
DR   ProteomicsDB; 48903; -.
DR   Antibodypedia; 25833; 388 antibodies.
DR   DNASU; 50846; -.
DR   Ensembl; ENST00000649637; ENSP00000497483; ENSG00000139549.
DR   GeneID; 50846; -.
DR   KEGG; hsa:50846; -.
DR   UCSC; uc001rtf.4; human.
DR   CTD; 50846; -.
DR   DisGeNET; 50846; -.
DR   GeneCards; DHH; -.
DR   GeneReviews; DHH; -.
DR   HGNC; HGNC:2865; DHH.
DR   HPA; ENSG00000139549; Tissue enriched (testis).
DR   MalaCards; DHH; -.
DR   MIM; 233420; phenotype.
DR   MIM; 605423; gene.
DR   MIM; 607080; phenotype.
DR   neXtProt; NX_O43323; -.
DR   OpenTargets; ENSG00000139549; -.
DR   Orphanet; 242; 46,XY complete gonadal dysgenesis.
DR   Orphanet; 168563; 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome.
DR   PharmGKB; PA27326; -.
DR   VEuPathDB; HostDB:ENSG00000139549.2; -.
DR   eggNOG; KOG3638; Eukaryota.
DR   GeneTree; ENSGT00940000161132; -.
DR   HOGENOM; CLU_034686_0_0_1; -.
DR   InParanoid; O43323; -.
DR   OMA; HWAFGPV; -.
DR   OrthoDB; 1169356at2759; -.
DR   PhylomeDB; O43323; -.
DR   TreeFam; TF106458; -.
DR   PathwayCommons; O43323; -.
DR   Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR   Reactome; R-HSA-5358346; Hedgehog ligand biogenesis.
DR   Reactome; R-HSA-5362798; Release of Hh-Np from the secreting cell.
DR   Reactome; R-HSA-5632681; Ligand-receptor interactions.
DR   Reactome; R-HSA-5632684; Hedgehog 'on' state.
DR   Reactome; R-HSA-5635838; Activation of SMO.
DR   Reactome; R-HSA-5658034; HHAT G278V doesn't palmitoylate Hh-Np.
DR   Reactome; R-HSA-9690406; Transcriptional regulation of testis differentiation.
DR   SignaLink; O43323; -.
DR   BioGRID-ORCS; 50846; 9 hits in 995 CRISPR screens.
DR   EvolutionaryTrace; O43323; -.
DR   GeneWiki; Desert_hedgehog_protein; -.
DR   GenomeRNAi; 50846; -.
DR   Pharos; O43323; Tbio.
DR   PRO; PR:O43323; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; O43323; protein.
DR   Bgee; ENSG00000139549; Expressed in tibial nerve and 86 other tissues.
DR   Genevisible; O43323; HS.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR   GO; GO:0005113; F:patched binding; IBA:GO_Central.
DR   GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0001708; P:cell fate specification; IBA:GO_Central.
DR   GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR   GO; GO:0033327; P:Leydig cell differentiation; IEA:Ensembl.
DR   GO; GO:0030238; P:male sex determination; IEA:Ensembl.
DR   GO; GO:0042552; P:myelination; IEA:Ensembl.
DR   GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR   GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR   GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR   GO; GO:0050810; P:regulation of steroid biosynthetic process; IEA:Ensembl.
DR   GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR   GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
DR   GO; GO:0007224; P:smoothened signaling pathway; IBA:GO_Central.
DR   GO; GO:0007286; P:spermatid development; IEA:Ensembl.
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   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.
PE   1: Evidence at protein level;
KW   3D-structure; Autocatalytic cleavage; Calcium; Cell membrane;
KW   Developmental protein; Disease variant; Hydrolase; Lipoprotein; Membrane;
KW   Metal-binding; Palmitate; Protease; Reference proteome; Secreted; Signal;
KW   Zinc.
FT   SIGNAL          1..22
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..396
FT                   /note="Desert hedgehog protein"
FT                   /id="PRO_0000013244"
FT   CHAIN           23..198
FT                   /note="Desert hedgehog protein N-product"
FT                   /id="PRO_0000013245"
FT   CHAIN           199..396
FT                   /note="Desert hedgehog protein C-product"
FT                   /id="PRO_0000013246"
FT   METAL           90
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           91
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           91
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           96
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           126
FT                   /note="Calcium 1; via carbonyl oxygen"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           127
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           127
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           130
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           132
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFR,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           141
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFQ,
FT                   ECO:0007744|PDB:2WFR, ECO:0007744|PDB:2WG3,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           148
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFQ,
FT                   ECO:0007744|PDB:2WFR, ECO:0007744|PDB:2WG3,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   METAL           183
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:19561611,
FT                   ECO:0000269|PubMed:20519495, ECO:0007744|PDB:2WFQ,
FT                   ECO:0007744|PDB:2WFR, ECO:0007744|PDB:2WG3,
FT                   ECO:0007744|PDB:3N1G, ECO:0007744|PDB:3N1Q"
FT   SITE            198..199
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000250"
FT   SITE            244
FT                   /note="Involved in cholesterol transfer"
FT                   /evidence="ECO:0000250"
FT   SITE            268
FT                   /note="Involved in auto-cleavage"
FT                   /evidence="ECO:0000250"
FT   SITE            271
FT                   /note="Essential for auto-cleavage"
FT                   /evidence="ECO:0000250"
FT   LIPID           23
FT                   /note="N-palmitoyl cysteine"
FT                   /evidence="ECO:0000250"
FT   LIPID           198
FT                   /note="Cholesterol glycine ester"
FT                   /evidence="ECO:0000250"
FT   VARIANT         162
FT                   /note="L -> P (in SRXY7; dbSNP:rs111033589)"
FT                   /evidence="ECO:0000269|PubMed:15356051"
FT                   /id="VAR_054873"
FT   CONFLICT        177
FT                   /note="E -> G (in Ref. 3; AAB03398)"
FT                   /evidence="ECO:0000305"
FT   STRAND          48..52
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   TURN            57..60
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           73..76
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          85..87
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          92..94
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           95..97
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           101..117
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          123..127
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           140..143
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          146..151
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           156..158
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           159..168
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          172..178
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   STRAND          181..185
FT                   /evidence="ECO:0007829|PDB:2WFQ"
FT   HELIX           192..195
FT                   /evidence="ECO:0007829|PDB:2WFQ"
SQ   SEQUENCE   396 AA;  43577 MW;  FCE4FB21972C3AD5 CRC64;
     MALLTNLLPL CCLALLALPA QSCGPGRGPV GRRRYARKQL VPLLYKQFVP GVPERTLGAS
     GPAEGRVARG SERFRDLVPN YNPDIIFKDE ENSGADRLMT ERCKERVNAL AIAVMNMWPG
     VRLRVTEGWD EDGHHAQDSL HYEGRALDIT TSDRDRNKYG LLARLAVEAG FDWVYYESRN
     HVHVSVKADN SLAVRAGGCF PGNATVRLWS GERKGLRELH RGDWVLAADA SGRVVPTPVL
     LFLDRDLQRR ASFVAVETEW PPRKLLLTPW HLVFAARGPA PAPGDFAPVF ARRLRAGDSV
     LAPGGDALRP ARVARVAREE AVGVFAPLTA HGTLLVNDVL ASCYAVLESH QWAHRAFAPL
     RLLHALGALL PGGAVQPTGM HWYSRLLYRL AEELLG
//
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