HTRA2_DROME
ID HTRA2_DROME Reviewed; 422 AA.
AC Q9VFJ3;
DT 28-JUL-2009, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Serine protease HTRA2, mitochondrial {ECO:0000303|PubMed:18259196};
DE EC=3.4.21.108;
DE AltName: Full=High temperature requirement protein A2 {ECO:0000250|UniProtKB:O43464};
DE Short=DmHtrA2 {ECO:0000312|EMBL:BAE72064.1};
DE Short=HtrA2 {ECO:0000303|PubMed:18259196};
DE AltName: Full=Omi stress-regulated endoprotease {ECO:0000303|PubMed:18259196};
DE Short=dOmi {ECO:0000303|PubMed:18259196};
DE Contains:
DE RecName: Full=Serine protease HTRA2, mitochondrial, long {ECO:0000303|PubMed:18259196};
DE Contains:
DE RecName: Full=Serine protease HTRA2, mitochondrial, short {ECO:0000303|PubMed:18259196};
DE Flags: Precursor;
GN Name=HtrA2 {ECO:0000312|FlyBase:FBgn0038233};
GN Synonyms=Omi/HtrA2 {ECO:0000303|PubMed:18259196}; ORFNames=CG8464;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAE72064.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND
RP DEVELOPMENTAL STAGE.
RC TISSUE=Embryo {ECO:0000269|PubMed:17397804};
RX PubMed=17397804; DOI=10.1016/j.bbrc.2007.03.079;
RA Igaki T., Suzuki Y., Tokushige N., Aonuma H., Takahashi R., Miura M.;
RT "Evolution of mitochondrial cell death pathway: Proapoptotic role of
RT HtrA2/Omi in Drosophila.";
RL Biochem. Biophys. Res. Commun. 356:993-997(2007).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DEVELOPMENTAL STAGE, CLEAVAGE, AND
RP MUTAGENESIS OF ALA-79; ALA-80; ALA-92 AND ALA-93.
RC STRAIN=Berkeley {ECO:0000269|PubMed:17557079};
RC TISSUE=Testis {ECO:0000269|PubMed:17557079};
RX PubMed=17557079; DOI=10.1038/sj.emboj.7601745;
RA Challa M., Malladi S., Pellock B.J., Dresnek D., Varadarajan S., Yin Y.W.,
RA White K., Bratton S.B.;
RT "Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic
RT serine protease.";
RL EMBO J. 26:3144-3156(2007).
RN [3] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION,
RP INTERACTION WITH TH, SUBCELLULAR LOCATION, CLEAVAGE, AND MUTAGENESIS OF
RP ALA-75 AND SER-266.
RC STRAIN=Berkeley {ECO:0000269|PubMed:18259196};
RC TISSUE=Testis {ECO:0000269|PubMed:18259196};
RX PubMed=18259196; DOI=10.1038/cdd.2008.19;
RA Khan F.S., Fujioka M., Datta P., Fernandes-Alnemri T., Jaynes J.B.,
RA Alnemri E.S.;
RT "The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in
RT Drosophila.";
RL Cell Death Differ. 15:1073-1083(2008).
RN [4] {ECO:0000312|EMBL:AAF55062.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [5] {ECO:0000312|EMBL:AAF55062.1}
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [6] {ECO:0000312|EMBL:AAL68074.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley {ECO:0000269|PubMed:12537569};
RC TISSUE=Testis {ECO:0000269|PubMed:12537569};
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [7]
RP INTERACTION WITH PINK1 AND RHO-7.
RX PubMed=19048081; DOI=10.1242/dmm.000109;
RA Whitworth A.J., Lee J.R., Ho V.M., Flick R., Chowdhury R., McQuibban G.A.;
RT "Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's
RT disease factors Pink1 and Parkin.";
RL Dis. Model. Mech. 1:168-174(2008).
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. Can
CC antagonize antiapoptotic activity of th by directly inducing the
CC degradation of th. {ECO:0000269|PubMed:17397804,
CC ECO:0000269|PubMed:17557079, ECO:0000269|PubMed:18259196}.
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: Interacts with th/DIAP1 (via BIR 2 domain) (PubMed:18259196).
CC Interacts with Pink1 and rho-7 (PubMed:19048081).
CC {ECO:0000269|PubMed:18259196, ECO:0000269|PubMed:19048081}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space
CC {ECO:0000269|PubMed:17397804, ECO:0000269|PubMed:18259196}; Single-pass
CC membrane protein {ECO:0000255}. Mitochondrion membrane
CC {ECO:0000269|PubMed:18259196}; Single-pass membrane protein
CC {ECO:0000255}. Note=Predominantly present in the intermembrane space
CC (PubMed:17397804, PubMed:18259196). Released into the cytosol following
CC apoptotic stimuli, such as UV treatment (PubMed:17397804). The
CC extramitochondrial protein does not diffuse throughout the cytosol but
CC stays near the mitochondria (PubMed:17397804).
CC {ECO:0000269|PubMed:17397804, ECO:0000269|PubMed:18259196}.
CC -!- DEVELOPMENTAL STAGE: Expressed during all stages of development; high
CC in embryos, declined in larvae and pupae and high again in adults.
CC {ECO:0000269|PubMed:17397804, ECO:0000269|PubMed:17557079}.
CC -!- PTM: Ubiquitinated by th, thereby antagonizing induced cell death.
CC -!- PTM: Autoproteolytically cleaved into active forms in the mitochondria.
CC {ECO:0000269|PubMed:17557079, ECO:0000269|PubMed:18259196}.
CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000255}.
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DR EMBL; AB112473; BAE72064.1; -; mRNA.
DR EMBL; AE014297; AAF55062.1; -; Genomic_DNA.
DR EMBL; AY075206; AAL68074.1; -; mRNA.
DR RefSeq; NP_001262565.1; NM_001275636.1.
DR RefSeq; NP_650366.1; NM_142109.2.
DR AlphaFoldDB; Q9VFJ3; -.
DR SMR; Q9VFJ3; -.
DR BioGRID; 66831; 9.
DR DIP; DIP-23879N; -.
DR IntAct; Q9VFJ3; 3.
DR MINT; Q9VFJ3; -.
DR STRING; 7227.FBpp0303078; -.
DR MEROPS; S01.476; -.
DR PaxDb; Q9VFJ3; -.
DR PRIDE; Q9VFJ3; -.
DR EnsemblMetazoa; FBtr0082987; FBpp0082446; FBgn0038233.
DR EnsemblMetazoa; FBtr0330045; FBpp0303078; FBgn0038233.
DR GeneID; 41756; -.
DR KEGG; dme:Dmel_CG8464; -.
DR UCSC; CG8464-RA; d. melanogaster.
DR CTD; 27429; -.
DR FlyBase; FBgn0038233; HtrA2.
DR VEuPathDB; VectorBase:FBgn0038233; -.
DR eggNOG; KOG1320; Eukaryota.
DR GeneTree; ENSGT00940000155108; -.
DR HOGENOM; CLU_020120_6_0_1; -.
DR InParanoid; Q9VFJ3; -.
DR OMA; DTRHFDY; -.
DR OrthoDB; 630723at2759; -.
DR PhylomeDB; Q9VFJ3; -.
DR BRENDA; 3.4.21.108; 1994.
DR Reactome; R-DME-1474228; Degradation of the extracellular matrix.
DR BioGRID-ORCS; 41756; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 41756; -.
DR PRO; PR:Q9VFJ3; -.
DR Proteomes; UP000000803; Chromosome 3R.
DR Bgee; FBgn0038233; Expressed in testis and 23 other tissues.
DR ExpressionAtlas; Q9VFJ3; baseline and differential.
DR Genevisible; Q9VFJ3; DM.
DR GO; GO:0005829; C:cytosol; IDA:FlyBase.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:FlyBase.
DR GO; GO:0016006; C:Nebenkern; IDA:FlyBase.
DR GO; GO:0008233; F:peptidase activity; IDA:FlyBase.
DR GO; GO:0017171; F:serine hydrolase activity; HDA:FlyBase.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:FlyBase.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0035234; P:ectopic germ cell programmed cell death; IMP:FlyBase.
DR GO; GO:0007005; P:mitochondrion organization; IMP:FlyBase.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:FlyBase.
DR GO; GO:2001056; P:positive regulation of cysteine-type endopeptidase activity; IDA:FlyBase.
DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR GO; GO:0042981; P:regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:FlyBase.
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; Direct protein sequencing; Hydrolase; Membrane; Mitochondrion;
KW Protease; Reference proteome; Serine protease; Transit peptide;
KW Transmembrane; Transmembrane helix; Ubl conjugation; Zymogen.
FT TRANSIT 1..17
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT PROPEP 18..74
FT /evidence="ECO:0000255, ECO:0000269|PubMed:18259196"
FT /id="PRO_0000379939"
FT CHAIN 75..422
FT /note="Serine protease HTRA2, mitochondrial, long"
FT /evidence="ECO:0000269|PubMed:18259196"
FT /id="PRO_0000379940"
FT CHAIN 94..422
FT /note="Serine protease HTRA2, mitochondrial, short"
FT /evidence="ECO:0000269|PubMed:18259196"
FT /id="PRO_0000379941"
FT TRANSMEM 64..82
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 325..410
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT REGION 29..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 139..302
FT /note="Serine protease"
FT /evidence="ECO:0000255"
FT MOTIF 75..78
FT /note="IAP-binding"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:18259196"
FT MOTIF 94..97
FT /note="IAP-binding"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:18259196"
FT ACT_SITE 157
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:O43464"
FT ACT_SITE 189
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:O43464"
FT ACT_SITE 266
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:18259196"
FT MUTAGEN 75
FT /note="A->P: Significant reduction of th binding."
FT /evidence="ECO:0000269|PubMed:18259196"
FT MUTAGEN 79
FT /note="A->W: Reduction in levels of cleavage; when
FT associated with Trp-80."
FT /evidence="ECO:0000269|PubMed:17557079"
FT MUTAGEN 80
FT /note="A->W: Reduction in levels of cleavage; when
FT associated with Trp-79."
FT /evidence="ECO:0000269|PubMed:17557079"
FT MUTAGEN 92
FT /note="A->D: Reduction in levels of cleavage; when
FT associated with Asp-93."
FT /evidence="ECO:0000269|PubMed:17557079"
FT MUTAGEN 93
FT /note="A->D: Reduction in levels of cleavage; when
FT associated with Asp-92."
FT /evidence="ECO:0000269|PubMed:17557079"
FT MUTAGEN 266
FT /note="S->A: Destroys protease active site."
FT /evidence="ECO:0000269|PubMed:18259196"
SQ SEQUENCE 422 AA; 46000 MW; 7BDD72E4CA86B5D5 CRC64;
MALRGSHRLE VIFKRCIASP VLHSHAANRR SSQLAIKEGD PNSNGNSGQY QQNGEQKEKG
WRRLVRFFVP FSLGAVVSAA IIQREDLTPT IAASKMTGRR RDFNFIADVV AGCADSVVYI
EIKDTRHFDY FSGQPITASN GSGFIIEQNG LILTNAHVVI NKPHTMVQVR LSDGRTFPAT
IEDVDQTSDL ATLRIQVNNL SVMRLGKSST LRSGEWVVAL GSPLALSNTV TAGVISSTQR
ASQELGLRNR DINYLQTDAA ITFGNSGGPL VNLDGEAIGV NSMKVTAGIS FAIPIDYVKV
FLERAAEKRK KGSAYKTGYP VKRYMGITML TLTPDILFEL KSRSQNMPSN LTHGVLVWKV
IVGSPAHSGG LQPGDIVTHI NKKEIKNSSD VYDALADNSK TLDIVILRGV KQMHVTITPE
DP
