HTRA2_MOUSE
ID HTRA2_MOUSE Reviewed; 458 AA.
AC Q9JIY5; Q9R108;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-MAR-2002, sequence version 2.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Serine protease HTRA2, mitochondrial;
DE EC=3.4.21.108;
DE AltName: Full=High temperature requirement protein A2;
DE Short=HtrA2;
DE AltName: Full=Omi stress-regulated endoprotease;
DE AltName: Full=Serine protease 25;
DE AltName: Full=Serine proteinase OMI;
DE Flags: Precursor;
GN Name=Htra2; Synonyms=Omi, Prss25;
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].
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=10971580; DOI=10.1046/j.1432-1327.2000.01589.x;
RA Gray C.W., Ward R.V., Karran E.H., Turconi S., Rowles A., Viglienghi D.,
RA Southan C., Barton A., Fantom K.G., West A., Savopoulos J.W., Hassan N.J.,
RA Clinkenbeard H., Hanning C., Amegadzie B., Davis J.B., Dingwall C.,
RA Livi G.P., Creasy C.L.;
RT "Characterization of human HtrA2, a novel serine protease involved in the
RT mammalian cellular stress response.";
RL Eur. J. Biochem. 267:5699-5710(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RA Faccio L., Fusco C., Zervos A.S.;
RT "Characterization of the mouse homolog of Omi serine protease.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION IN APOPTOSIS, AND MUTAGENESIS OF ALA-134; ALA-137 AND SER-306.
RX PubMed=11604410; DOI=10.1074/jbc.m109891200;
RA Verhagen A.M., Silke J., Ekert P.G., Pakusch M., Kaufmann H.,
RA Connolly L.M., Day C.L., Tikoo A., Burke R., Wrobel C., Moritz R.L.,
RA Simpson R.J., Vaux D.L.;
RT "HtrA2 promotes cell death through its serine protease activity and its
RT ability to antagonize inhibitor of apoptosis proteins.";
RL J. Biol. Chem. 277:445-454(2002).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Pancreas, Spleen, and
RC Testis;
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 [5]
RP INTERACTION WITH AREL1.
RX PubMed=23479728; DOI=10.1074/jbc.m112.436113;
RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y.,
RA Chae H.D., Shin D.Y.;
RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that
RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2,
RT and ARTS.";
RL J. Biol. Chem. 288:12014-12021(2013).
CC -!- FUNCTION: Serine protease that shows proteolytic activity against a
CC non-specific substrate beta-casein. Promotes or induces cell death
CC either by direct binding to and inhibition of BIRC proteins (also
CC called inhibitor of apoptosis proteins, IAPs), leading to an increase
CC in caspase activity, or by a BIRC inhibition-independent, caspase-
CC independent and serine protease activity-dependent mechanism. Cleaves
CC THAP5 and promotes its degradation during apoptosis (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:11604410}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cleavage of non-polar aliphatic amino-acids at the P1
CC position, with a preference for Val, Ile and Met. At the P2 and P3
CC positions, Arg is selected most strongly with a secondary preference
CC for other hydrophilic residues.; EC=3.4.21.108;
CC -!- SUBUNIT: Homotrimer. Interacts with MXI2. Interacts with THAP5 under
CC apoptotic conditions (By similarity). The mature protein, but not the
CC precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (By
CC similarity). Interacts with BIRC6/bruce (By similarity). Interacts with
CC AREL1 (via HECT domain); in the cytoplasm following induction of
CC apoptosis (PubMed:23479728). {ECO:0000250,
CC ECO:0000269|PubMed:23479728}.
CC -!- INTERACTION:
CC Q9JIY5; O35387: Hax1; NbExp=3; IntAct=EBI-2365838, EBI-642449;
CC Q9JIY5; Q99MS3: Mpv17l; NbExp=2; IntAct=EBI-2365838, EBI-15727135;
CC Q9JIY5; Q99MS3-1: Mpv17l; NbExp=3; IntAct=EBI-2365838, EBI-15727082;
CC Q9JIY5; Q99MS3-3: Mpv17l; NbExp=2; IntAct=EBI-2365838, EBI-15727109;
CC Q9JIY5; Q60989: Xiap; NbExp=2; IntAct=EBI-2365838, EBI-517478;
CC Q9JIY5; P98170: XIAP; Xeno; NbExp=4; IntAct=EBI-2365838, EBI-517127;
CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space. Mitochondrion
CC membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}.
CC Note=Predominantly present in the intermembrane space. Released into
CC the cytosol following apoptotic stimuli, such as UV treatment, and
CC stimulation of mitochondria with BID.
CC -!- DOMAIN: The mature N-terminus is involved in the interaction with XIAP.
CC -!- DOMAIN: The PDZ domain mediates interaction with MXI2.
CC -!- PTM: Autoproteolytically activated. {ECO:0000250|UniProtKB:O43464}.
CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}.
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DR EMBL; AF164513; AAF89534.1; -; mRNA.
DR EMBL; AF175324; AAD50499.1; -; mRNA.
DR CCDS; CCDS20267.1; -.
DR RefSeq; NP_062726.3; NM_019752.3.
DR AlphaFoldDB; Q9JIY5; -.
DR SMR; Q9JIY5; -.
DR BioGRID; 211100; 20.
DR DIP; DIP-41272N; -.
DR IntAct; Q9JIY5; 8.
DR MINT; Q9JIY5; -.
DR STRING; 10090.ENSMUSP00000087073; -.
DR ChEMBL; CHEMBL3259508; -.
DR MEROPS; S01.278; -.
DR iPTMnet; Q9JIY5; -.
DR PhosphoSitePlus; Q9JIY5; -.
DR REPRODUCTION-2DPAGE; Q9JIY5; -.
DR EPD; Q9JIY5; -.
DR jPOST; Q9JIY5; -.
DR MaxQB; Q9JIY5; -.
DR PaxDb; Q9JIY5; -.
DR PeptideAtlas; Q9JIY5; -.
DR PRIDE; Q9JIY5; -.
DR ProteomicsDB; 273283; -.
DR Antibodypedia; 3554; 776 antibodies from 42 providers.
DR DNASU; 64704; -.
DR Ensembl; ENSMUST00000089645; ENSMUSP00000087073; ENSMUSG00000068329.
DR GeneID; 64704; -.
DR KEGG; mmu:64704; -.
DR UCSC; uc009clu.3; mouse.
DR CTD; 27429; -.
DR MGI; MGI:1928676; Htra2.
DR VEuPathDB; HostDB:ENSMUSG00000068329; -.
DR eggNOG; KOG1320; Eukaryota.
DR GeneTree; ENSGT00940000155108; -.
DR InParanoid; Q9JIY5; -.
DR OMA; WRYATEQ; -.
DR OrthoDB; 630723at2759; -.
DR PhylomeDB; Q9JIY5; -.
DR TreeFam; TF323480; -.
DR BRENDA; 3.4.21.108; 3474.
DR BioGRID-ORCS; 64704; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Htra2; mouse.
DR PRO; PR:Q9JIY5; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q9JIY5; protein.
DR Bgee; ENSMUSG00000068329; Expressed in renal corpuscle and 258 other tissues.
DR ExpressionAtlas; Q9JIY5; baseline and differential.
DR Genevisible; Q9JIY5; MM.
DR GO; GO:0035631; C:CD40 receptor complex; IDA:BHF-UCL.
DR GO; GO:0000785; C:chromatin; ISO:MGI.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005856; C:cytoskeleton; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0005758; C:mitochondrial intermembrane space; ISO:MGI.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:1905370; C:serine-type endopeptidase complex; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0008233; F:peptidase activity; IMP:ParkinsonsUK-UCL.
DR GO; GO:0004252; F:serine-type endopeptidase activity; ISO:MGI.
DR GO; GO:0008236; F:serine-type peptidase activity; ISO:MGI.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:MGI.
DR GO; GO:0007628; P:adult walking behavior; IMP:MGI.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; ISO:MGI.
DR GO; GO:0034605; P:cellular response to heat; ISO:MGI.
DR GO; GO:0035458; P:cellular response to interferon-beta; ISO:MGI.
DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISO:MGI.
DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl.
DR GO; GO:0030900; P:forebrain development; IMP:MGI.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:MGI.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; ISO:MGI.
DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI.
DR GO; GO:0060548; P:negative regulation of cell death; ISO:MGI.
DR GO; GO:1904924; P:negative regulation of mitophagy in response to mitochondrial depolarization; IMP:ParkinsonsUK-UCL.
DR GO; GO:0048666; P:neuron development; IMP:MGI.
DR GO; GO:0019742; P:pentacyclic triterpenoid metabolic process; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:2001269; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; ISO:MGI.
DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; ISO:MGI.
DR GO; GO:0010822; P:positive regulation of mitochondrion organization; ISO:MGI.
DR GO; GO:0012501; P:programmed cell death; ISO:MGI.
DR GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR GO; GO:0006508; P:proteolysis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR Gene3D; 2.30.42.10; -; 1.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR041489; PDZ_6.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR001940; Peptidase_S1C.
DR Pfam; PF17820; PDZ_6; 1.
DR PRINTS; PR00834; PROTEASES2C.
DR SMART; SM00228; PDZ; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50106; PDZ; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Hydrolase; Membrane; Mitochondrion; Protease;
KW Reference proteome; Serine protease; Transit peptide; Transmembrane;
KW Transmembrane helix; Zymogen.
FT TRANSIT 1..31
FT /note="Mitochondrion"
FT PROPEP 32..133
FT /evidence="ECO:0000255"
FT /id="PRO_0000026947"
FT CHAIN 134..458
FT /note="Serine protease HTRA2, mitochondrial"
FT /id="PRO_0000026948"
FT TRANSMEM 105..125
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 364..446
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT REGION 166..342
FT /note="Serine protease"
FT MOTIF 134..137
FT /note="IAP-binding motif"
FT /evidence="ECO:0000250"
FT ACT_SITE 198
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:O43464"
FT ACT_SITE 228
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:O43464"
FT ACT_SITE 306
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:O43464"
FT MUTAGEN 134
FT /note="A->G: Loss of interaction with XIAP."
FT /evidence="ECO:0000269|PubMed:11604410"
FT MUTAGEN 137
FT /note="A->I: Stronger interaction with XIAP third BIR
FT domain."
FT /evidence="ECO:0000269|PubMed:11604410"
FT MUTAGEN 306
FT /note="S->A: Loss of protease activity."
FT /evidence="ECO:0000269|PubMed:11604410"
FT CONFLICT 449
FT /note="T -> I (in Ref. 1; AAF89534)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 458 AA; 49348 MW; C1E77346FB8D75BD CRC64;
MAALKAGRGA NWSLRAWRAL GGIFWRKPPL LAPDLRALLT SGTPDSQIWM TYGTPSLPAQ
VPEGFLASRA DLTSRTPDLW ARLNVGTSGS SDQEARRSPG SRRREWLAVA VGAGGAVVLL
LWGWGRGLST VLAAVPAPPP TSPRSQYNFI ADVVEKTAPA VVYIEILDRH PFSGREVPIS
NGSGFVVASD GLIVTNAHVV ADRRRVRVRL PSGDTYEAMV TAVDPVADIA TLRIQTKEPL
PTLPLGRSAD VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQN NVEYIQTDAA
IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS WFGTSGSQRR
YIGVMMLTLT PSILIELQLR EPSFPDVQHG VLIHKVILGS PAHRAGLRPG DVILAIGEKL
AQNAEDVYEA VRTQSQLAVR IRRGSETLTL YVTPEVTE
