PHEX_MOUSE
ID PHEX_MOUSE Reviewed; 749 AA.
AC P70669; P97439;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Phosphate-regulating neutral endopeptidase PHEX {ECO:0000305};
DE AltName: Full=Metalloendopeptidase homolog PEX;
DE EC=3.4.24.- {ECO:0000250|UniProtKB:P78562};
DE AltName: Full=Phosphate regulating neutral endopeptidase;
DE AltName: Full=Vitamin D-resistant hypophosphatemic rickets protein;
DE AltName: Full=X-linked hypophosphatemia protein;
DE Short=HYP;
GN Name=Phex; Synonyms=Hyp, Pex;
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 [MRNA].
RX PubMed=8812412; DOI=10.1006/geno.1996.0421;
RA Du L., Desbarats M., Viel J., Glorieux F.H., Cawthorn C., Ecarot B.;
RT "cDNA cloning of the murine Pex gene implicated in X-linked
RT hypophosphatemia and evidence for expression in bone.";
RL Genomics 36:22-28(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=9063736; DOI=10.1093/hmg/6.2.165;
RA Strom T.M., Francis F., Lorenz B., Boeddrich A., Econs M.J., Lehrach H.,
RA Meitinger T.;
RT "Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked
RT hypophosphatemia.";
RL Hum. Mol. Genet. 6:165-171(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=9077527; DOI=10.1172/jci119276;
RA Beck L., Soumounou Y., Martel J., Krishnamurthy G., Gauthier C.,
RA Goodyer C.G., Tenenhouse H.S.;
RT "Pex/PEX tissue distribution and evidence for a deletion in the 3' region
RT of the Pex gene in X-linked hypophosphatemic mice.";
RL J. Clin. Invest. 99:1200-1209(1997).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=11159866; DOI=10.1210/endo.142.2.7976;
RA Miao D., Bai X., Panda D., McKee M., Karaplis A., Goltzman D.;
RT "Osteomalacia in hyp mice is associated with abnormal phex expression and
RT with altered bone matrix protein expression and deposition.";
RL Endocrinology 142:926-939(2001).
RN [5]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
RP GLYCOSYLATION.
RX PubMed=11811562; DOI=10.1359/jbmr.2002.17.2.311;
RA Thompson D.L., Sabbagh Y., Tenenhouse H.S., Roche P.C., Drezner M.K.,
RA Salisbury J.L., Grande J.P., Poeschla E.M., Kumar R.;
RT "Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular
RT localization in osteoblasts.";
RL J. Bone Miner. Res. 17:311-320(2002).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=18597632; DOI=10.1359/jbmr.080601;
RA Addison W.N., Nakano Y., Loisel T., Crine P., McKee M.D.;
RT "MEPE-ASARM peptides control extracellular matrix mineralization by binding
RT to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM.";
RL J. Bone Miner. Res. 23:1638-1649(2008).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP FUNCTION.
RX PubMed=26051469; DOI=10.1016/j.bone.2015.05.030;
RA Zelenchuk L.V., Hedge A.M., Rowe P.S.;
RT "Age dependent regulation of bone-mass and renal function by the MEPE
RT ASARM-motif.";
RL Bone 79:131-142(2015).
CC -!- FUNCTION: Peptidase that cleaves SIBLING (small integrin-binding
CC ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating
CC their biological activity (By similarity). Cleaves ASARM peptides
CC between Ser and Glu or Asp residues (By similarity). Regulates
CC osteogenic cell differentiation and bone mineralization through the
CC cleavage of the MEPE-derived ASARM peptide (PubMed:11159866,
CC PubMed:18597632, PubMed:26051469). Promotes dentin mineralization and
CC renal phosphate reabsorption by cleaving DMP1- and MEPE-derived ASARM
CC peptides (PubMed:26051469). Inhibits the cleavage of MEPE by
CC CTSB/cathepsin B thus preventing MEPE degradation (By similarity).
CC {ECO:0000250|UniProtKB:P78562, ECO:0000269|PubMed:11159866,
CC ECO:0000269|PubMed:26051469, ECO:0000305|PubMed:18597632}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P78562};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P78562};
CC -!- SUBUNIT: Interacts with MEPE; the interaction is zinc-dependent (via
CC ASARM motif). {ECO:0000250|UniProtKB:P78562}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11811562};
CC Single-pass type II membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed in bone, specifically in the osteoid and
CC in osteocytes (PubMed:11159866, PubMed:18597632). Expressed in teeth,
CC specifically in odontoblasts and ameloblasts (PubMed:11811562).
CC Expressed moderately by macrophages in the liver and has minimal
CC expression in brown adipose tissue (PubMed:11811562). Also expressed in
CC suprabasal layers of the skin (PubMed:11811562).
CC {ECO:0000269|PubMed:11159866, ECO:0000269|PubMed:11811562,
CC ECO:0000269|PubMed:18597632}.
CC -!- DEVELOPMENTAL STAGE: Detected at 16 and 18 days post coitum (dpc) in
CC vertebrae osteoblasts. Detected in calvarial tissue and in the stratum
CC spinosum and granulosum of the overlaying epidermis at 18 dpc. Detected
CC at postnatal day 14 in osteoblasts and osteocytes of the calvarium.
CC Detected in tibias at postnatal day 14 in osteoblasts and a lesser
CC degree in osteocytes, however by postnatal day 84 it is detected in
CC osteocytes in compact bone. Detected in teeth at postnatal day 14 in
CC odontoblasts and ameloblasts. By postnatal day 84, expression can still
CC be detected in odontoblasts however little to no expression can be
CC detected in ameloblasts. Detected at 18 dpc at moderate levels in
CC macrophages within the liver, with minimal expression in brown adipose
CC tissue. Detected at 18 dpc in suprabasal layers of the skin.
CC {ECO:0000269|PubMed:11811562}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11811562}.
CC -!- SIMILARITY: Belongs to the peptidase M13 family. {ECO:0000255|PROSITE-
CC ProRule:PRU01233, ECO:0000305}.
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DR EMBL; U49908; AAC36502.1; -; mRNA.
DR EMBL; U73910; AAC25962.1; -; mRNA.
DR EMBL; U73912; AAC25964.1; -; Genomic_DNA.
DR EMBL; U73913; AAC25965.1; -; Genomic_DNA.
DR EMBL; U73914; AAC25966.1; -; Genomic_DNA.
DR EMBL; U73911; AAC25963.1; -; Genomic_DNA.
DR EMBL; U73915; AAC25967.1; -; Genomic_DNA.
DR EMBL; U75646; AAB47750.1; -; mRNA.
DR CCDS; CCDS30497.1; -.
DR RefSeq; NP_035207.1; NM_011077.2.
DR AlphaFoldDB; P70669; -.
DR SMR; P70669; -.
DR BioGRID; 202143; 1.
DR STRING; 10090.ENSMUSP00000078863; -.
DR MEROPS; M13.091; -.
DR GlyGen; P70669; 8 sites.
DR iPTMnet; P70669; -.
DR PhosphoSitePlus; P70669; -.
DR PaxDb; P70669; -.
DR PRIDE; P70669; -.
DR ProteomicsDB; 287699; -.
DR Antibodypedia; 24481; 137 antibodies from 26 providers.
DR DNASU; 18675; -.
DR Ensembl; ENSMUST00000079945; ENSMUSP00000078863; ENSMUSG00000057457.
DR GeneID; 18675; -.
DR KEGG; mmu:18675; -.
DR UCSC; uc009ury.1; mouse.
DR CTD; 5251; -.
DR MGI; MGI:107489; Phex.
DR VEuPathDB; HostDB:ENSMUSG00000057457; -.
DR eggNOG; KOG3624; Eukaryota.
DR GeneTree; ENSGT00940000157313; -.
DR HOGENOM; CLU_006187_4_1_1; -.
DR InParanoid; P70669; -.
DR OMA; YSSYYWK; -.
DR OrthoDB; 282463at2759; -.
DR PhylomeDB; P70669; -.
DR TreeFam; TF315192; -.
DR BRENDA; 3.4.24.B15; 3474.
DR BioGRID-ORCS; 18675; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Phex; mouse.
DR PRO; PR:P70669; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; P70669; protein.
DR Bgee; ENSMUSG00000057457; Expressed in molar tooth and 73 other tissues.
DR ExpressionAtlas; P70669; baseline and differential.
DR Genevisible; P70669; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; IBA:GO_Central.
DR GO; GO:0060348; P:bone development; IEA:Ensembl.
DR GO; GO:0030282; P:bone mineralization; IMP:MGI.
DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0071305; P:cellular response to vitamin D; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0042476; P:odontogenesis; IMP:MGI.
DR GO; GO:0019637; P:organophosphate metabolic process; IMP:MGI.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
DR GO; GO:0060416; P:response to growth hormone; IEA:Ensembl.
DR GO; GO:1990418; P:response to insulin-like growth factor stimulus; IEA:Ensembl.
DR GO; GO:1904383; P:response to sodium phosphate; IEA:Ensembl.
DR CDD; cd08662; M13; 1.
DR Gene3D; 1.10.1380.10; -; 1.
DR Gene3D; 3.40.390.10; -; 1.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR000718; Peptidase_M13.
DR InterPro; IPR018497; Peptidase_M13_C.
DR InterPro; IPR042089; Peptidase_M13_dom_2.
DR InterPro; IPR008753; Peptidase_M13_N.
DR PANTHER; PTHR11733; PTHR11733; 1.
DR Pfam; PF01431; Peptidase_M13; 1.
DR Pfam; PF05649; Peptidase_M13_N; 1.
DR PRINTS; PR00786; NEPRILYSIN.
DR PROSITE; PS51885; NEPRILYSIN; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW Biomineralization; Cell membrane; Disulfide bond; Glycoprotein; Hydrolase;
KW Membrane; Metal-binding; Metalloprotease; Protease; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..749
FT /note="Phosphate-regulating neutral endopeptidase PHEX"
FT /id="PRO_0000078229"
FT TOPO_DOM 1..20
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 21..37
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 38..749
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 53..749
FT /note="Peptidase M13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT ACT_SITE 581
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT ACT_SITE 646
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT BINDING 580
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 584
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233,
FT ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 642
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 238
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 263
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 290
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 301
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 377
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 484
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 736
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..59
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 77..733
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 85..693
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 142..406
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT DISULFID 617..746
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01233"
FT CONFLICT 430
FT /note="D -> V (in Ref. 3; AAB47750)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 749 AA; 86419 MW; A88FA481C376C18A CRC64;
MEAETGSTME TGKGTNRGIR IALALFIGGT LVLGTLLFLV SQGLLSFQAK QEYCLKPECI
EAAAAIMSKV NLSVDPCENF FRFACDGWIS NNPIPEDMPS YGVYPWLRHN VDLKLKALLE
KSVSRRRDTE AVQKAKILYS SCMNEKAIEK ADAKPLLHIL RHSPFRWPVL EANIGPEGVW
SERKFSLLQT LATFRGQYSN SVFIRLYVSP DDKASNEHIL KLDQATLSLA VREDFLDNTT
EAKSYRDALY KFMVDTAVLL GANSSRAEHD MKSVLRLEIK IAEIMIPHEN RTSEAMYNKM
NISELSAMIP QFDWLGYIKK VIDTRLYPHL KDIGPSENVV VRVPQYFKDL FRILGAERKK
TIANYLVWRM VYSRIPNLSR RFQYRWLEFS RVIQGTTTLL PQWDKCVNFI ESALPYVVGK
MFVNVHFQED KKEMMEELIE GVRWAFIDML EKENEWMDAG TKRKAQEKAR AVLAKVGYPE
FIMNDTYVNE DLKAIKFSES DYFGNVLQTR KYLAQSDFFW LRKAVPKTEW FTNPTTVNAF
YSASTNQIRF PAGELQKPFF WGTEYPRSLS YGAIGVIVGH EFTHGFDNNG RKYDKNGNLD
PWWSVESEEK FKEKTKCMIN QYSNYYWKKA GLNVKGKRTL GENIADNGGL REAFRAYRKW
INDRRQGVEE PLLPGITFTN NQLFFLSYAH VRCNSYRPEA AREQVQIGAH SPPQFRVNGA
ISNFEEFQKA FNCPRNSTMN RGADSCRLW
