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   25-JAN-2012, entry version 114.
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   MEDLINE=20489872; PubMed=11017805;
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   VARIANT GDXYM 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   [6]
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   -!- SUBCELLULAR LOCATION: Desert hedgehog protein N-product: Cell
CC       membrane; Lipid-anchor; Extracellular side (By similarity).
CC       Note=The N-terminal peptide remains associated with the cell
CC       surface (By similarity).
CC   -!- SUBCELLULAR LOCATION: Desert hedgehog protein C-product: Secreted,
CC       extracellular space (By similarity). Note=The C-terminal peptide
CC       diffuses from the cell (By similarity).
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   -!- DISEASE: Defects in DHH may be the cause of partial gonadal
CC       dysgenesis with minifascicular neuropathy 46,XY (PGD)
CC       [MIM:607080]. PGD is characterized by the presence of a testis on
CC       one side and a streak or an absent gonad at the other, persistence
CC       of Muellerian duct structures, and a variable degree of genital
CC       ambiguity.
CC   -!- DISEASE: Defects in DHH may be the cause of complete pure gonadal
CC       dysgenesis 46,XY type (GDXYM) [MIM:233420]; also known as male-
CC       limited gonadal dysgenesis 46,XY. GDXYM is a type of hypogonadism
CC       in which no functional gonads are present to induce puberty in an
CC       externally female person whose karyotype is then found to be XY.
CC       The gonads are found to be non-functional streaks.
CC   -!- SIMILARITY: Belongs to the hedgehog family.
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DR   EMBL; AB010994; BAA24866.1; -; Genomic_DNA.
DR   EMBL; BC033507; AAH33507.1; -; mRNA.
DR   EMBL; U59748; AAB03398.1; -; mRNA.
DR   IPI; IPI00011978; -.
DR   PIR; G02735; G02735.
DR   RefSeq; NP_066382.1; NM_021044.2.
DR   UniGene; Hs.524382; -.
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; 39-189, 199-345.
DR   DIP; DIP-48538N; -.
DR   STRING; O43323; -.
DR   MEROPS; C46.004; -.
DR   PRIDE; O43323; -.
DR   Ensembl; ENST00000266991; ENSP00000266991; ENSG00000139549.
DR   GeneID; 50846; -.
DR   KEGG; hsa:50846; -.
DR   UCSC; uc001rtf.1; human.
DR   CTD; 50846; -.
DR   GeneCards; GC12M049483; -.
DR   H-InvDB; HIX0201908; -.
DR   HGNC; HGNC:2865; DHH.
DR   HPA; CAB034386; -.
DR   MIM; 233420; phenotype.
DR   MIM; 605423; gene.
DR   MIM; 607080; phenotype.
DR   neXtProt; NX_O43323; -.
DR   Orphanet; 242; 46,XY complete gonadal dysgenesis.
DR   Orphanet; 168563; 46,XY gonadal dysgenesis - motor and sensory neuropathy.
DR   Orphanet; 1770; Gonadal dysgenesis, XY type - associated anomalies.
DR   PharmGKB; PA27326; -.
DR   eggNOG; prNOG08414; -.
DR   GeneTree; ENSGT00390000001117; -.
DR   HOGENOM; HBG403179; -.
DR   HOVERGEN; HBG005480; -.
DR   InParanoid; O43323; -.
DR   OMA; YKQFVPS; -.
DR   OrthoDB; EOG46WZ8G; -.
DR   PhylomeDB; O43323; -.
DR   Pathway_Interaction_DB; hedgehog_2pathway; Signaling events mediated by the Hedgehog family.
DR   NextBio; 53313; -.
DR   ArrayExpress; O43323; -.
DR   Bgee; O43323; -.
DR   CleanEx; HS_DHH; -.
DR   Genevestigator; O43323; -.
DR   GermOnline; ENSG00000139549; Homo sapiens.
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:0005515; F:protein binding; IPI:BHF-UCL.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   InterPro; IPR009045; Hedgehog/DD-peptidase.
DR   InterPro; IPR003586; Hedgehog_hint_C.
DR   InterPro; IPR003587; Hedgehog_hint_N.
DR   InterPro; IPR000320; Hedgehog_signaling_dom.
DR   InterPro; IPR001657; Peptidase_C46.
DR   InterPro; IPR001767; Peptidase_C46_hint.
DR   Gene3D; G3DSA:3.30.1380.10; Hedgehog/DD-pept_Zn-bd; 1.
DR   KO; K11990; -.
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_sig_N; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Autocatalytic cleavage; Cell membrane;
KW   Complete proteome; Developmental protein; Disease mutation; Hydrolase;
KW   Lipoprotein; Membrane; Palmitate; Protease; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL        1     22       Potential.
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   SITE        198    199       Cleavage; by autolysis (By similarity).
FT   SITE        244    244       Involved in cholesterol transfer (By
FT                                similarity).
FT   SITE        268    268       Involved in auto-cleavage (By
FT                                similarity).
FT   SITE        271    271       Essential for auto-cleavage (By
FT                                similarity).
FT   LIPID        23     23       N-palmitoyl cysteine (By similarity).
FT   LIPID       198    198       Cholesterol glycine ester (By
FT                                similarity).
FT   VARIANT     162    162       L -> P (in GDXYM).
FT                                /FTId=VAR_054873.
FT   CONFLICT    177    177       E -> G (in Ref. 3; AAB03398).
FT   HELIX        73     76
FT   STRAND       85     87
FT   HELIX       101    117
FT   STRAND      123    127
FT   HELIX       140    142
FT   STRAND      146    151
FT   HELIX       156    158
FT   HELIX       162    168
FT   STRAND      173    178
FT   STRAND      181    185
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
//