DHH_MOUSE
ID DHH_MOUSE Reviewed; 396 AA.
AC Q61488;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Desert hedgehog protein {ECO:0000305};
DE Short=DHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=HHG-3;
DE Contains:
DE RecName: Full=Desert hedgehog protein N-product;
DE Flags: Precursor;
GN Name=Dhh {ECO:0000312|MGI:MGI:94891};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/Sv;
RX PubMed=7916661; DOI=10.1016/0092-8674(93)90627-3;
RA Echelard Y., Epstein D.J., St Jacques B., Shen L., Mohler J., McMahon J.A.,
RA McMahon A.P.;
RT "Sonic hedgehog, a member of a family of putative signaling molecules, is
RT implicated in the regulation of CNS polarity.";
RL Cell 75:1417-1430(1993).
RN [2]
RP PROTEIN SEQUENCE OF 56-66, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 120-168.
RX PubMed=7720571; DOI=10.1242/dev.120.11.3339;
RA Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R.,
RA Seldin M.F., Fallon J.F., Beachy P.A.;
RT "Products, genetic linkage and limb patterning activity of a murine
RT hedgehog gene.";
RL Development 120:3339-3353(1994).
RN [4]
RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=8805249; DOI=10.1016/s0960-9822(02)00480-3;
RA Bitgood M.J., Shen L., McMahon A.P.;
RT "Sertoli cell signaling by Desert hedgehog regulates the male germline.";
RL Curr. Biol. 6:298-304(1996).
RN [5]
RP FUNCTION.
RX PubMed=9811851; DOI=10.1073/pnas.95.23.13630;
RA Carpenter D., Stone D.M., Brush J., Ryan A., Armanini M., Frantz G.,
RA Rosenthal A., de Sauvage F.J.;
RT "Characterization of two patched receptors for the vertebrate hedgehog
RT protein family.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:13630-13634(1998).
RN [6]
RP FUNCTION.
RX PubMed=10482238; DOI=10.1016/s0896-6273(01)80030-1;
RA Parmantier E., Lynn B., Lawson D., Turmaine M., Namini S.S.,
RA Chakrabarti L., McMahon A.P., Jessen K.R., Mirsky R.;
RT "Schwann cell-derived Desert hedgehog controls the development of
RT peripheral nerve sheaths.";
RL Neuron 23:713-724(1999).
RN [7]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=11090455; DOI=10.1095/biolreprod63.6.1825;
RA Clark A.M., Garland K.K., Russell L.D.;
RT "Desert hedgehog (Dhh) gene is required in the mouse testis for formation
RT of adult-type Leydig cells and normal development of peritubular cells and
RT seminiferous tubules.";
RL Biol. Reprod. 63:1825-1838(2000).
RN [8]
RP DEVELOPMENTAL STAGE, AND FUNCTION.
RX PubMed=32151560; DOI=10.1016/j.ydbio.2020.03.003;
RA Fulmer D., Toomer K.A., Glover J., Guo L., Moore K., Moore R., Stairley R.,
RA Gensemer C., Abrol S., Rumph M.K., Emetu F., Lipschutz J.H., McDowell C.,
RA Bian J., Wang C., Beck T., Wessels A., Renault M.A., Norris R.A.;
RT "Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by
RT organizing smooth muscle actin.";
RL Dev. Biol. 463:26-38(2020).
RN [9]
RP FUNCTION.
RX PubMed=33063110; DOI=10.1093/cvr/cvaa285;
RA Hollier P.L., Chapouly C., Diop A., Guimbal S., Cornuault L., Gadeau A.P.,
RA Renault M.A.;
RT "Full-length Dhh and N-terminal Shh act as competitive antagonists to
RT regulate angiogenesis and vascular permeability.";
RL Cardiovasc. Res. 117:2489-2501(2021).
CC -!- FUNCTION: [Desert hedgehog protein]: The C-terminal part of the desert
CC hedgehog protein precursor displays an autoproteolysis and a
CC cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein into two parts (DhhN
CC and DhhC) followed by the covalent attachment of a cholesterol moiety
CC to the C-terminal of the newly generated DhhN (By similarity). Both
CC activities occur in the reticulum endoplasmic (By similarity).
CC Functions in cell-cell mediated juxtacrine signaling (By similarity).
CC Promotes endothelium integrity (PubMed:33063110). Binds to PTCH1
CC receptor, which functions in association with smoothened (SMO), to
CC activate the transcription of target genes in endothelial cells
CC (PubMed:33063110). In Schwann cells, controls the development of the
CC peripheral nerve sheath and the transition of mesenchymal cells to form
CC the epithelium-like structure of the perineurial tube
CC (PubMed:10482238). {ECO:0000250|UniProtKB:O43323,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:10482238,
CC ECO:0000269|PubMed:33063110}.
CC -!- FUNCTION: [Desert hedgehog protein N-product]: The dually lipidated
CC desert hedgehog protein N-product (DhhNp) is essential for a variety of
CC patterning events during development (By similarity). Binds to the
CC patched (PTCH1) receptor, which functions in association with
CC smoothened (SMO), to activate the transcription of target genes
CC (PubMed:9811851). Required for normal testis development and
CC spermatogenesis, namely for the formation of adult-type Leydig cells
CC and normal development of peritubular cells and seminiferous tubules
CC (PubMed:8805249, PubMed:11090455). Activates primary cilia signaling on
CC neighboring valve interstitial cells through a paracrine mechanism
CC (PubMed:32151560). May induce motor neurons in lateral neural tube and
CC may have a polarizing activity. Prevents the desert hedgehog protein
CC precursor binding to PTCH1 (By similarity). Binds PTCH2
CC (PubMed:9811851). {ECO:0000250|UniProtKB:O43323,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:11090455,
CC ECO:0000269|PubMed:32151560, ECO:0000269|PubMed:8805249,
CC ECO:0000269|PubMed:9811851}.
CC -!- CATALYTIC ACTIVITY: [Desert hedgehog protein]:
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: [Desert hedgehog protein N-product]: Multimer.
CC {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBUNIT: Interacts with BOC and CDON. Interacts with HHIP.
CC {ECO:0000250|UniProtKB:O43323}.
CC -!- SUBCELLULAR LOCATION: [Desert hedgehog protein N-product]: Cell
CC membrane {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- SUBCELLULAR LOCATION: [Desert hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q15465}. Secreted {ECO:0000269|PubMed:33063110}.
CC Cell membrane {ECO:0000250|UniProtKB:O43323}. Note=Co-localizes with
CC HHAT in the ER and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
CC -!- TISSUE SPECIFICITY: Expressed in adult testes (PubMed:8805249). Not
CC expressed in limb buds. {ECO:0000269|PubMed:8805249}.
CC -!- DEVELOPMENTAL STAGE: First detected at 11.5 dpc in the presumptive
CC testis (PubMed:8805249). No expression in the ovary at this or any
CC later time (PubMed:8805249). At 12.5 dpc testis expression is confined
CC to Sertoli cells and is not detected in precursors of the androgen-
CC producing interstitial somatic cells (the Leydig cells)
CC (PubMed:8805249). At E13 expressed by Schwann cell precursors both in
CC the dorsal and ventral roots and in the emerging spinal nerves
CC (PubMed:10482238). Expressed in Schwann cells of newborn
CC (PubMed:10482238). Expressed primarily within the valve endocardium at
CC E15.5 with lower levels of expression within the trabeculated
CC endothelium, primary atrial septum and epicardium (PubMed:32151560).
CC Expressed within the valve endocardium at embryonic, fetal and neonatal
CC timepoints with evidence of protein diffusion into the interstitium
CC (PubMed:32151560). Primarily expressed within the atrialis aspect of
CC the anterior and posterior mitral leaflets with the highest signal
CC present at the valve tip (PubMed:32151560).
CC {ECO:0000269|PubMed:10482238, ECO:0000269|PubMed:32151560,
CC ECO:0000269|PubMed:8805249}.
CC -!- DOMAIN: [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:0000250|UniProtKB:O43323}.
CC -!- DOMAIN: [Desert hedgehog protein]: The C-terminal domain regulates the
CC auto-processing and controls the juxtacrine signaling.
CC {ECO:0000250|UniProtKB:O43323}.
CC -!- PTM: [Desert hedgehog protein]: Partially autoproteolyzed (By
CC similarity). The C-terminal domain displays an autoproteolysis activity
CC and a cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein and covalent
CC attachment of a cholesterol moiety to the C-terminal of the newly
CC generated N-terminal fragment (DhhN) (By similarity).
CC {ECO:0000250|UniProtKB:O43323, ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Desert hedgehog protein N-product]: N-palmitoylation by HHAT of
CC DhhN is required for desert hedgehog protein N-product multimerization
CC and full activity (By similarity). {ECO:0000250|UniProtKB:Q62226}.
CC -!- DISRUPTION PHENOTYPE: Female mice homozygous for the Dhh gene are fully
CC viable and fertile, whereas male mice are viable but infertile, owing
CC to a complete absence of mature sperm (PubMed:8805249). Male mice
CC exhibit a dramatic reduction in testicular growth (PubMed:8805249). The
CC severity of the phenotype varies depending upon the genetic background
CC of the mice (PubMed:8805249). The majority of the Dhh-null males are
CC pseudohermaphrodites with a blind vaginal opening and evidence of
CC teats. These mice show anastomotic seminiferous tubules, pertitubular
CC cell abnormalities, and absence of adult-type Leydig cells
CC (PubMed:11090455). {ECO:0000269|PubMed:11090455,
CC ECO:0000269|PubMed:8805249}.
CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
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DR EMBL; X76292; CAA53924.1; -; Genomic_DNA.
DR CCDS; CCDS27810.1; -.
DR PIR; B49425; B49425.
DR RefSeq; NP_031883.1; NM_007857.5.
DR AlphaFoldDB; Q61488; -.
DR SMR; Q61488; -.
DR STRING; 10090.ENSMUSP00000023737; -.
DR MEROPS; C46.004; -.
DR iPTMnet; Q61488; -.
DR PhosphoSitePlus; Q61488; -.
DR PaxDb; Q61488; -.
DR PRIDE; Q61488; -.
DR ProteomicsDB; 279356; -.
DR Antibodypedia; 25833; 399 antibodies from 29 providers.
DR DNASU; 13363; -.
DR Ensembl; ENSMUST00000023737; ENSMUSP00000023737; ENSMUSG00000023000.
DR GeneID; 13363; -.
DR KEGG; mmu:13363; -.
DR UCSC; uc007xoh.2; mouse.
DR CTD; 50846; -.
DR MGI; MGI:94891; Dhh.
DR VEuPathDB; HostDB:ENSMUSG00000023000; -.
DR eggNOG; KOG3638; Eukaryota.
DR GeneTree; ENSGT00940000161132; -.
DR HOGENOM; CLU_034686_0_0_1; -.
DR InParanoid; Q61488; -.
DR OMA; CGPGPRY; -.
DR OrthoDB; 1169356at2759; -.
DR PhylomeDB; Q61488; -.
DR TreeFam; TF106458; -.
DR Reactome; R-MMU-5358346; Hedgehog ligand biogenesis.
DR Reactome; R-MMU-5362798; Release of Hh-Np from the secreting cell.
DR Reactome; R-MMU-5632681; Ligand-receptor interactions.
DR Reactome; R-MMU-5635838; Activation of SMO.
DR BioGRID-ORCS; 13363; 5 hits in 74 CRISPR screens.
DR ChiTaRS; Dhh; mouse.
DR PRO; PR:Q61488; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q61488; protein.
DR Bgee; ENSMUSG00000023000; Expressed in sciatic nerve and 94 other tissues.
DR ExpressionAtlas; Q61488; baseline and differential.
DR Genevisible; Q61488; MM.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
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; ISS:UniProtKB.
DR GO; GO:0005113; F:patched binding; IPI:BHF-UCL.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; ISS: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:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0033327; P:Leydig cell differentiation; IMP:MGI.
DR GO; GO:0030238; P:male sex determination; IGI:MGI.
DR GO; GO:0042552; P:myelination; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IDA:MGI.
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; IGI:MGI.
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; IDA:MGI.
DR GO; GO:0007286; P:spermatid development; IMP:MGI.
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 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Direct protein sequencing; Endoplasmic reticulum; Golgi apparatus;
KW Hydrolase; Lipoprotein; Membrane; Metal-binding; Palmitate; Protease;
KW Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..396
FT /note="Desert hedgehog protein"
FT /id="PRO_0000013247"
FT CHAIN 23..198
FT /note="Desert hedgehog protein N-product"
FT /id="PRO_0000013248"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 96
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 130
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 148
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT SITE 198..199
FT /note="Cleavage; by autolysis"
FT SITE 244
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 268
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 271
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 23
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:O43323"
FT LIPID 198
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
SQ SEQUENCE 396 AA; 43542 MW; AFFEB051BE950FD8 CRC64;
MALPASLLPL CCLALLALSA QSCGPGRGPV GRRRYVRKQL VPLLYKQFVP SMPERTLGAS
GPAEGRVTRG SERFRDLVPN YNPDIIFKDE ENSGADRLMT ERCKERVNAL AIAVMNMWPG
VRLRVTEGWD EDGHHAQDSL HYEGRALDIT TSDRDRNKYG LLARLAVEAG FDWVYYESRN
HIHVSVKADN SLAVRAGGCF PGNATVRLRS GERKGLRELH RGDWVLAADA AGRVVPTPVL
LFLDRDLQRR ASFVAVETER PPRKLLLTPW HLVFAARGPA PAPGDFAPVF ARRLRAGDSV
LAPGGDALQP ARVARVAREE AVGVFAPLTA HGTLLVNDVL ASCYAVLESH QWAHRAFAPL
RLLHALGALL PGGAVQPTGM HWYSRLLYRL AEELMG
