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 13-FEB-2019, entry version 176. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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 RT human 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 RT project: 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 RP AND 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 RP 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 RT conserved 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. 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 CC patterning events during development. May function as a CC spermatocyte survival factor in the testes. Essential for testes CC development. CC -!- SUBUNIT: Interacts with BOC and CDON. Interacts with HHIP. CC {ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495}. CC -!- INTERACTION: CC Q9BWV1:BOC; NbExp=2; IntAct=EBI-11667804, EBI-718555; CC Q4KMG0:CDON; NbExp=2; IntAct=EBI-11667804, EBI-7016840; CC 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 CC side {ECO:0000250}. Note=The N-terminal peptide remains associated CC with the cell surface. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Desert hedgehog protein C-product: Secreted, CC extracellular space {ECO:0000250}. Note=The C-terminal peptide CC diffuses from the cell. {ECO:0000250}. CC -!- DOMAIN: The desert hedgehog protein N-product binds calcium and CC zinc ions; this stabilizes the protein fold and is essential for CC protein-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 CC and a cholesterol transferase activity. Both activities result in CC the cleavage of the full-length protein and covalent attachment of CC a cholesterol moiety to the C-terminal of the newly generated N- CC terminal fragment (N-product). This covalent modification appears CC to play an essential role in restricting the spatial distribution CC of the protein activity to the cell surface. The N-product is the CC active species in both local and long-range signaling, whereas the CC C-product has no signaling activity (By similarity). CC {ECO:0000250}. CC -!- DISEASE: Partial gonadal dysgenesis with minifascicular neuropathy CC 46,XY (PGD) [MIM:607080]: Characterized by the presence of a CC testis on one side and a streak or an absent gonad at the other, CC persistence of Muellerian duct structures, and a variable degree CC of genital ambiguity. {ECO:0000269|PubMed:11017805}. Note=The CC disease may be caused by mutations affecting the gene represented CC in this entry. CC -!- DISEASE: 46,XY sex reversal 7 (SRXY7) [MIM:233420]: A disorder of CC sex development. Affected individuals have a 46,XY karyotype but CC present as phenotypically normal females. SRXY7 patients have no CC functional gonads. {ECO:0000269|PubMed:15356051}. Note=The disease CC may be caused by mutations affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the hedgehog family. {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; 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 UniGene; Hs.524382; -. DR UniGene; Hs.533776; -. 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 ProteinModelPortal; O43323; -. DR SMR; O43323; -. DR BioGrid; 119151; 7. DR DIP; DIP-48538N; -. DR IntAct; O43323; 3. DR STRING; 9606.ENSP00000266991; -. DR MEROPS; C46.004; -. DR iPTMnet; O43323; -. DR PhosphoSitePlus; O43323; -. DR BioMuta; DHH; -. DR PaxDb; O43323; -. DR PeptideAtlas; O43323; -. DR PRIDE; O43323; -. DR ProteomicsDB; 48903; -. DR Ensembl; ENST00000266991; ENSP00000266991; ENSG00000139549. DR Ensembl; ENST00000649637; ENSP00000497483; ENSG00000139549. DR GeneID; 50846; -. DR KEGG; hsa:50846; -. DR UCSC; uc001rtf.4; human. DR CTD; 50846; -. DR DisGeNET; 50846; -. DR EuPathDB; HostDB:ENSG00000139549.2; -. DR GeneCards; DHH; -. DR GeneReviews; DHH; -. DR HGNC; HGNC:2865; DHH. 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 eggNOG; KOG3638; Eukaryota. DR eggNOG; ENOG410XQA3; LUCA. DR GeneTree; ENSGT00940000161132; -. DR HOGENOM; HOG000233428; -. DR HOVERGEN; HBG005480; -. DR InParanoid; O43323; -. DR KO; K11990; -. DR OMA; EQQNGIH; -. DR OrthoDB; 1169356at2759; -. DR PhylomeDB; O43323; -. DR TreeFam; TF106458; -. 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 abrogates palmitoylation of Hh-Np. DR SignaLink; O43323; -. DR SIGNOR; O43323; -. DR EvolutionaryTrace; O43323; -. DR GeneWiki; Desert_hedgehog_protein; -. DR GenomeRNAi; 50846; -. DR PRO; PR:O43323; -. DR Proteomes; UP000005640; Chromosome 12. DR Bgee; ENSG00000139549; Expressed in 73 organ(s), highest expression level in tibial nerve. DR Genevisible; O43323; HS. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro. DR GO; GO:0007275; P:multicellular organism development; IEA:UniProtKB-KW. 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 Complete proteome; Developmental protein; Disease mutation; Hydrolase; KW Lipoprotein; Membrane; Metal-binding; Palmitate; Protease; KW Reference proteome; Secreted; Signal; Zinc. FT SIGNAL 1 22 {ECO:0000255}. FT CHAIN 23 396 Desert hedgehog protein. FT /FTId=PRO_0000013244. FT CHAIN 23 198 Desert hedgehog protein N-product. FT /FTId=PRO_0000013245. FT CHAIN 199 396 Desert hedgehog protein C-product. FT /FTId=PRO_0000013246. FT METAL 90 90 Calcium 1. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 91 91 Calcium 1. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 91 91 Calcium 2. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 96 96 Calcium 1. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 126 126 Calcium 1; via carbonyl oxygen. FT {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 127 127 Calcium 1. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 127 127 Calcium 2. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 130 130 Calcium 2. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 132 132 Calcium 2. {ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 141 141 Zinc. {ECO:0000244|PDB:2WFQ, FT ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:2WG3, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 148 148 Zinc. {ECO:0000244|PDB:2WFQ, FT ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:2WG3, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT METAL 183 183 Zinc. {ECO:0000244|PDB:2WFQ, FT ECO:0000244|PDB:2WFR, FT ECO:0000244|PDB:2WG3, FT ECO:0000244|PDB:3N1G, FT ECO:0000244|PDB:3N1Q, FT ECO:0000269|PubMed:19561611, FT ECO:0000269|PubMed:20519495}. FT SITE 198 199 Cleavage; by autolysis. {ECO:0000250}. FT SITE 244 244 Involved in cholesterol transfer. FT {ECO:0000250}. FT SITE 268 268 Involved in auto-cleavage. {ECO:0000250}. FT SITE 271 271 Essential for auto-cleavage. FT {ECO:0000250}. FT LIPID 23 23 N-palmitoyl cysteine. {ECO:0000250}. FT LIPID 198 198 Cholesterol glycine ester. {ECO:0000250}. FT VARIANT 162 162 L -> P (in SRXY7; dbSNP:rs111033589). FT {ECO:0000269|PubMed:15356051}. FT /FTId=VAR_054873. FT CONFLICT 177 177 E -> G (in Ref. 3; AAB03398). FT {ECO:0000305}. FT STRAND 48 52 {ECO:0000244|PDB:2WFQ}. FT TURN 57 60 {ECO:0000244|PDB:2WFQ}. FT HELIX 73 76 {ECO:0000244|PDB:2WFQ}. FT STRAND 85 87 {ECO:0000244|PDB:2WFQ}. FT STRAND 92 94 {ECO:0000244|PDB:2WFQ}. FT HELIX 95 97 {ECO:0000244|PDB:2WFQ}. FT HELIX 101 117 {ECO:0000244|PDB:2WFQ}. FT STRAND 123 127 {ECO:0000244|PDB:2WFQ}. FT HELIX 140 143 {ECO:0000244|PDB:2WFQ}. FT STRAND 146 151 {ECO:0000244|PDB:2WFQ}. FT HELIX 156 158 {ECO:0000244|PDB:2WFQ}. FT HELIX 159 168 {ECO:0000244|PDB:2WFQ}. FT STRAND 172 178 {ECO:0000244|PDB:2WFQ}. FT STRAND 181 185 {ECO:0000244|PDB:2WFQ}. FT HELIX 192 195 {ECO:0000244|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 //