HTRA2_HUMAN
ID HTRA2_HUMAN Reviewed; 458 AA.
AC O43464; Q9HBZ4; Q9P0Y3; Q9P0Y4;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 2.
DT 03-AUG-2022, entry version 224.
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 Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF SER-306.
RX PubMed=10644717; DOI=10.1074/jbc.275.4.2581;
RA Faccio L., Fusco C., Chen A., Martinotti S., Bonventre J.V., Zervos A.S.;
RT "Characterization of a novel human serine protease that has extensive
RT homology to bacterial heat shock endoprotease HtrA and is regulated by
RT kidney ischemia.";
RL J. Biol. Chem. 275:2581-2588(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4), AND CHARACTERIZATION.
RC 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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Kidney;
RX PubMed=10995577; DOI=10.1006/geno.2000.6263;
RA Faccio L., Fusco C., Viel A., Zervos A.S.;
RT "Tissue-specific splicing of Omi stress-regulated endoprotease leads to an
RT inactive protease with a modified PDZ motif.";
RL Genomics 68:343-347(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 134-458, INTERACTION WITH XIAP, AND MUTAGENESIS OF
RP ALA-134.
RX PubMed=11583623; DOI=10.1016/s1097-2765(01)00341-0;
RA Suzuki Y., Imai Y., Nakayama H., Takahashi K., Takio K., Takahashi R.;
RT "A serine protease, HtrA2, is released from the mitochondria and interacts
RT with XIAP, inducing cell death.";
RL Mol. Cell 8:613-621(2001).
RN [7]
RP CHARACTERIZATION, AND PHOSPHORYLATION.
RX PubMed=10873535; DOI=10.1006/prep.2000.1240;
RA Savopoulos J.W., Carter P.S., Turconi S., Pettman G.R., Karran E.H.,
RA Gray C.W., Ward R.V., Jenkins O., Creasy C.L.;
RT "Expression, purification, and functional analysis of the human serine
RT protease HtrA2.";
RL Protein Expr. Purif. 19:227-234(2000).
RN [8]
RP FUNCTION, AND INTERACTION WITH BIRC6/BRUCE.
RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018;
RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.;
RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin
RT ligase.";
RL Mol. Cell 14:801-811(2004).
RN [9]
RP FUNCTION, AND INTERACTION WITH THAP5.
RX PubMed=19502560; DOI=10.1152/ajpheart.00234.2009;
RA Balakrishnan M.P., Cilenti L., Mashak Z., Popat P., Alnemri E.S.,
RA Zervos A.S.;
RT "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved
RT by the proapoptotic Omi/HtrA2 protease during cell death.";
RL Am. J. Physiol. 297:H643-H653(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
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).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 134-458, SUBUNIT, AND ACTIVE SITE.
RX PubMed=11967569; DOI=10.1038/nsb795;
RA Li W., Srinivasula S.M., Chai J., Li P., Wu J.W., Zhang Z., Alnemri E.S.,
RA Shi Y.;
RT "Structural insights into the pro-apoptotic function of mitochondrial
RT serine protease HtrA2/Omi.";
RL Nat. Struct. Biol. 9:436-441(2002).
RN [15]
RP INVOLVEMENT IN PARK13, VARIANTS SER-141 AND SER-399, AND CHARACTERIZATION
RP OF VARIANTS SER-141 AND SER-399.
RX PubMed=15961413; DOI=10.1093/hmg/ddi215;
RA Strauss K.M., Martins L.M., Plun-Favreau H., Marx F.P., Kautzmann S.,
RA Berg D., Gasser T., Wszolek Z., Mueller T., Bornemann A., Wolburg H.,
RA Downward J., Riess O., Schulz J.B., Krueger R.;
RT "Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's
RT disease.";
RL Hum. Mol. Genet. 14:2099-2111(2005).
RN [16]
RP INVOLVEMENT IN PARK13, VARIANTS PRO-72 AND SER-141, AND VARIANT PARK13
RP TRP-404.
RX PubMed=18401856; DOI=10.1002/humu.20713;
RA Bogaerts V., Nuytemans K., Reumers J., Pals P., Engelborghs S., Pickut B.,
RA Corsmit E., Peeters K., Schymkowitz J., De Deyn P.P., Cras P., Rousseau F.,
RA Theuns J., Van Broeckhoven C.;
RT "Genetic variability in the mitochondrial serine protease HTRA2 contributes
RT to risk for Parkinson disease.";
RL Hum. Mutat. 29:832-840(2008).
RN [17]
RP VARIANTS CYS-12; LEU-128; SER-141; SER-227 AND SER-399.
RX PubMed=18364387; DOI=10.1093/hmg/ddn096;
RA Simon-Sanchez J., Singleton A.B.;
RT "Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic
RT mutations in neurologically normal controls.";
RL Hum. Mol. Genet. 17:1988-1993(2008).
RN [18]
RP VARIANT SER-399.
RX PubMed=25422467; DOI=10.1073/pnas.1419581111;
RA Unal Gulsuner H., Gulsuner S., Mercan F.N., Onat O.E., Walsh T., Shahin H.,
RA Lee M.K., Dogu O., Kansu T., Topaloglu H., Elibol B., Akbostanci C.,
RA King M.C., Ozcelik T., Tekinay A.B.;
RT "Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential
RT tremor and Parkinson disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:18285-18290(2014).
RN [19]
RP INVOLVEMENT IN MGCA8, VARIANT MGCA8 GLN-404, AND CHARACTERIZATION OF
RP VARIANT MGCA8 GLN-404.
RX PubMed=27208207; DOI=10.1136/jmedgenet-2016-103922;
RA Mandel H., Saita S., Edvardson S., Jalas C., Shaag A., Goldsher D.,
RA Vlodavsky E., Langer T., Elpeleg O.;
RT "Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and
RT 3-methylglutaconic aciduria.";
RL J. Med. Genet. 53:690-696(2016).
RN [20]
RP VARIANT SER-399.
RX PubMed=27535533; DOI=10.1038/nature19057;
RG Exome Aggregation Consortium;
RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T.,
RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T.,
RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J.,
RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M.,
RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N.,
RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P.,
RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A.,
RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G.,
RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M.,
RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C.,
RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M.,
RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M.,
RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P.,
RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G.,
RA Daly M.J., MacArthur D.G.;
RT "Analysis of protein-coding genetic variation in 60,706 humans.";
RL Nature 536:285-291(2016).
RN [21]
RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER, AND CHARACTERIZATION OF
RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER.
RX PubMed=27696117; DOI=10.1007/s10545-016-9977-2;
RA Olahova M., Thompson K., Hardy S.A., Barbosa I.A., Besse A.,
RA Anagnostou M.E., White K., Davey T., Simpson M.A., Champion M., Enns G.,
RA Schelley S., Lightowlers R.N., Chrzanowska-Lightowlers Z.M., McFarland R.,
RA Deshpande C., Bonnen P.E., Taylor R.W.;
RT "Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome
RT associated with 3-methylglutaconic aciduria.";
RL J. Inherit. Metab. Dis. 40:121-130(2017).
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. Isoform 2 seems to
CC be proteolytically inactive. {ECO:0000269|PubMed:15200957,
CC ECO:0000269|PubMed:19502560}.
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. The mature protein, but not the precursor, binds
CC to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with
CC BIRC6/bruce. Interacts with AREL1 (via HECT domain); in the cytoplasm
CC following induction of apoptosis (PubMed:23479728).
CC {ECO:0000269|PubMed:11583623, ECO:0000269|PubMed:11967569,
CC ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560,
CC ECO:0000269|PubMed:23479728}.
CC -!- INTERACTION:
CC O43464; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-517086, EBI-25840993;
CC O43464; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-517086, EBI-25844820;
CC O43464; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-517086, EBI-14199987;
CC O43464; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-517086, EBI-25843552;
CC O43464; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-517086, EBI-9089489;
CC O43464; Q96CA5: BIRC7; NbExp=2; IntAct=EBI-517086, EBI-517623;
CC O43464; Q7Z7K6: CENPV; NbExp=3; IntAct=EBI-517086, EBI-1210604;
CC O43464; P02489: CRYAA; NbExp=3; IntAct=EBI-517086, EBI-6875961;
CC O43464; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-517086, EBI-25842815;
CC O43464; O00303: EIF3F; NbExp=3; IntAct=EBI-517086, EBI-711990;
CC O43464; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-517086, EBI-9246952;
CC O43464; Q13216-2: ERCC8; NbExp=3; IntAct=EBI-517086, EBI-16466949;
CC O43464; Q99871: HAUS7; NbExp=3; IntAct=EBI-517086, EBI-395719;
CC O43464; Q02363: ID2; NbExp=3; IntAct=EBI-517086, EBI-713450;
CC O43464; Q8IY31-2: IFT20; NbExp=3; IntAct=EBI-517086, EBI-11742277;
CC O43464; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-517086, EBI-743960;
CC O43464; Q6P597: KLC3; NbExp=3; IntAct=EBI-517086, EBI-1643885;
CC O43464; P57682: KLF3; NbExp=3; IntAct=EBI-517086, EBI-8472267;
CC O43464; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-517086, EBI-714379;
CC O43464; P08727: KRT19; NbExp=3; IntAct=EBI-517086, EBI-742756;
CC O43464; Q14525: KRT33B; NbExp=3; IntAct=EBI-517086, EBI-1049638;
CC O43464; Q1L5Z9: LONRF2; NbExp=3; IntAct=EBI-517086, EBI-2510853;
CC O43464; Q99683: MAP3K5; NbExp=3; IntAct=EBI-517086, EBI-476263;
CC O43464; Q8NA82: MARCHF10; NbExp=3; IntAct=EBI-517086, EBI-2341554;
CC O43464; Q8N594: MPND; NbExp=3; IntAct=EBI-517086, EBI-2512452;
CC O43464; Q8WY64: MYLIP; NbExp=3; IntAct=EBI-517086, EBI-6952711;
CC O43464; Q9P0J0: NDUFA13; NbExp=7; IntAct=EBI-517086, EBI-372742;
CC O43464; Q13562: NEUROD1; NbExp=3; IntAct=EBI-517086, EBI-3908303;
CC O43464; O15381-5: NVL; NbExp=3; IntAct=EBI-517086, EBI-18577082;
CC O43464; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-517086, EBI-1058491;
CC O43464; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-517086, EBI-25830200;
CC O43464; Q9NUU6: OTULINL; NbExp=3; IntAct=EBI-517086, EBI-6916492;
CC O43464; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-517086, EBI-11022007;
CC O43464; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-517086, EBI-6309018;
CC O43464; O14813: PHOX2A; NbExp=3; IntAct=EBI-517086, EBI-25844430;
CC O43464; O75925: PIAS1; NbExp=3; IntAct=EBI-517086, EBI-629434;
CC O43464; Q8WWB5: PIH1D2; NbExp=3; IntAct=EBI-517086, EBI-10232538;
CC O43464; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-517086, EBI-10293968;
CC O43464; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-517086, EBI-25835994;
CC O43464; P17980: PSMC3; NbExp=3; IntAct=EBI-517086, EBI-359720;
CC O43464; P57052: RBM11; NbExp=3; IntAct=EBI-517086, EBI-741332;
CC O43464; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-517086, EBI-749039;
CC O43464; Q96D59: RNF183; NbExp=3; IntAct=EBI-517086, EBI-743938;
CC O43464; Q96GQ5: RUSF1; NbExp=3; IntAct=EBI-517086, EBI-8636004;
CC O43464; Q8N488: RYBP; NbExp=3; IntAct=EBI-517086, EBI-752324;
CC O43464; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-517086, EBI-11528848;
CC O43464; Q9NR46: SH3GLB2; NbExp=3; IntAct=EBI-517086, EBI-749607;
CC O43464; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-517086, EBI-358489;
CC O43464; Q16637-3: SMN2; NbExp=3; IntAct=EBI-517086, EBI-395447;
CC O43464; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-517086, EBI-3942425;
CC O43464; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-517086, EBI-745958;
CC O43464; Q86WV5: TEN1; NbExp=3; IntAct=EBI-517086, EBI-2562799;
CC O43464; O95150: TNFSF15; NbExp=3; IntAct=EBI-517086, EBI-16355546;
CC O43464; Q6DKK2: TTC19; NbExp=4; IntAct=EBI-517086, EBI-948354;
CC O43464; Q495M9: USH1G; NbExp=3; IntAct=EBI-517086, EBI-8601749;
CC O43464; O75604-3: USP2; NbExp=3; IntAct=EBI-517086, EBI-10696113;
CC O43464; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-517086, EBI-2850578;
CC O43464; Q15007-2: WTAP; NbExp=3; IntAct=EBI-517086, EBI-25840023;
CC O43464; O00308: WWP2; NbExp=3; IntAct=EBI-517086, EBI-743923;
CC O43464; P98170: XIAP; NbExp=21; IntAct=EBI-517086, EBI-517127;
CC O43464; P24278: ZBTB25; NbExp=3; IntAct=EBI-517086, EBI-739899;
CC O43464; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-517086, EBI-749023;
CC O43464; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-517086, EBI-12010736;
CC O43464; O60304: ZNF500; NbExp=3; IntAct=EBI-517086, EBI-18234077;
CC O43464; O15535: ZSCAN9; NbExp=3; IntAct=EBI-517086, EBI-751531;
CC O43464; Q86V28; NbExp=3; IntAct=EBI-517086, EBI-10259496;
CC O43464; P02666: CSN2; Xeno; NbExp=7; IntAct=EBI-517086, EBI-5260183;
CC O43464; Q60855: Ripk1; Xeno; NbExp=2; IntAct=EBI-517086, EBI-529119;
CC PRO_0000026946; P02666: CSN2; Xeno; NbExp=2; IntAct=EBI-5271862, EBI-5260183;
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 caspase-8 truncated BID/tBID.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum
CC {ECO:0000269|PubMed:10644717}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=13B;
CC IsoId=O43464-1; Sequence=Displayed;
CC Name=2; Synonyms=D-Omi;
CC IsoId=O43464-2; Sequence=VSP_005359, VSP_005361;
CC Name=3; Synonyms=p7;
CC IsoId=O43464-3; Sequence=VSP_005360, VSP_005361;
CC Name=4; Synonyms=p4;
CC IsoId=O43464-4; Sequence=VSP_005362;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed.
CC {ECO:0000269|PubMed:10644717}.
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:0000269|PubMed:10873535}.
CC -!- DISEASE: 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248]: An
CC autosomal recessive inborn error of metabolism resulting in early
CC death. Clinical features include extreme hypertonia observed at birth,
CC alternating with hypotonia, subsequent appearance of extrapyramidal
CC symptoms, lack of psychomotor development, microcephaly, and
CC intractable seizures. Patients show lactic acidemia, 3-methylglutaconic
CC aciduria, intermittent neutropenia, and progressive brain atrophy.
CC {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Parkinson disease 13 (PARK13) [MIM:610297]: A complex
CC neurodegenerative disorder characterized by bradykinesia, resting
CC tremor, muscular rigidity and postural instability, as well as by a
CC clinically significant response to treatment with levodopa. The
CC pathology involves the loss of dopaminergic neurons in the substantia
CC nigra and the presence of Lewy bodies (intraneuronal accumulations of
CC aggregated proteins), in surviving neurons in various areas of the
CC brain. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HTRA2ID41879ch2p13.html";
CC ---------------------------------------------------------------------------
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DR EMBL; AF020760; AAB94569.2; -; mRNA.
DR EMBL; AF141305; AAF66596.1; -; mRNA.
DR EMBL; AF141306; AAF66597.1; -; mRNA.
DR EMBL; AF141307; AAF66598.1; -; mRNA.
DR EMBL; AF184911; AAG13126.1; -; mRNA.
DR EMBL; AC006544; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000096; AAH00096.1; -; mRNA.
DR CCDS; CCDS1951.1; -. [O43464-1]
DR CCDS; CCDS1952.1; -. [O43464-2]
DR RefSeq; NP_001308656.1; NM_001321727.1. [O43464-3]
DR RefSeq; NP_037379.1; NM_013247.4. [O43464-1]
DR RefSeq; NP_659540.1; NM_145074.2. [O43464-2]
DR PDB; 1LCY; X-ray; 2.00 A; A=134-458.
DR PDB; 2PZD; X-ray; 2.75 A; A/B=359-458.
DR PDB; 5FHT; X-ray; 1.95 A; A=134-458.
DR PDB; 5M3N; X-ray; 1.65 A; A=134-458.
DR PDB; 5M3O; X-ray; 1.70 A; A=134-458.
DR PDB; 5TNY; X-ray; 1.70 A; A=134-458.
DR PDB; 5TNZ; X-ray; 1.75 A; A=134-458.
DR PDB; 5TO0; X-ray; 1.90 A; A=134-458.
DR PDB; 5TO1; X-ray; 1.69 A; A=134-458.
DR PDB; 5WYN; X-ray; 2.05 A; A=134-458.
DR PDBsum; 1LCY; -.
DR PDBsum; 2PZD; -.
DR PDBsum; 5FHT; -.
DR PDBsum; 5M3N; -.
DR PDBsum; 5M3O; -.
DR PDBsum; 5TNY; -.
DR PDBsum; 5TNZ; -.
DR PDBsum; 5TO0; -.
DR PDBsum; 5TO1; -.
DR PDBsum; 5WYN; -.
DR AlphaFoldDB; O43464; -.
DR SASBDB; O43464; -.
DR SMR; O43464; -.
DR BioGRID; 118165; 283.
DR CORUM; O43464; -.
DR ELM; O43464; -.
DR IntAct; O43464; 252.
DR MINT; O43464; -.
DR STRING; 9606.ENSP00000258080; -.
DR BindingDB; O43464; -.
DR ChEMBL; CHEMBL4523137; -.
DR MEROPS; S01.278; -.
DR MoonDB; O43464; Predicted.
DR iPTMnet; O43464; -.
DR PhosphoSitePlus; O43464; -.
DR BioMuta; HTRA2; -.
DR OGP; O43464; -.
DR EPD; O43464; -.
DR jPOST; O43464; -.
DR MassIVE; O43464; -.
DR MaxQB; O43464; -.
DR PaxDb; O43464; -.
DR PeptideAtlas; O43464; -.
DR PRIDE; O43464; -.
DR ProteomicsDB; 48958; -. [O43464-1]
DR ProteomicsDB; 48959; -. [O43464-2]
DR ProteomicsDB; 48960; -. [O43464-3]
DR ProteomicsDB; 48961; -. [O43464-4]
DR TopDownProteomics; O43464-2; -. [O43464-2]
DR ABCD; O43464; 1 sequenced antibody.
DR Antibodypedia; 3554; 776 antibodies from 42 providers.
DR DNASU; 27429; -.
DR Ensembl; ENST00000258080.8; ENSP00000258080.3; ENSG00000115317.12. [O43464-1]
DR Ensembl; ENST00000352222.7; ENSP00000312893.3; ENSG00000115317.12. [O43464-2]
DR GeneID; 27429; -.
DR KEGG; hsa:27429; -.
DR MANE-Select; ENST00000258080.8; ENSP00000258080.3; NM_013247.5; NP_037379.1.
DR UCSC; uc002smi.2; human. [O43464-1]
DR CTD; 27429; -.
DR DisGeNET; 27429; -.
DR GeneCards; HTRA2; -.
DR HGNC; HGNC:14348; HTRA2.
DR HPA; ENSG00000115317; Low tissue specificity.
DR MalaCards; HTRA2; -.
DR MIM; 168600; phenotype.
DR MIM; 606441; gene.
DR MIM; 610297; phenotype.
DR MIM; 617248; phenotype.
DR neXtProt; NX_O43464; -.
DR OpenTargets; ENSG00000115317; -.
DR Orphanet; 505208; 3-methylglutaconic aciduria type 8.
DR Orphanet; 2828; Young-onset Parkinson disease.
DR PharmGKB; PA33836; -.
DR VEuPathDB; HostDB:ENSG00000115317; -.
DR eggNOG; KOG1320; Eukaryota.
DR GeneTree; ENSGT00940000155108; -.
DR HOGENOM; CLU_020120_6_0_1; -.
DR InParanoid; O43464; -.
DR OMA; WRYATEQ; -.
DR OrthoDB; 630723at2759; -.
DR PhylomeDB; O43464; -.
DR TreeFam; TF323480; -.
DR BRENDA; 3.4.21.108; 2681.
DR PathwayCommons; O43464; -.
DR SignaLink; O43464; -.
DR SIGNOR; O43464; -.
DR BioGRID-ORCS; 27429; 92 hits in 1081 CRISPR screens.
DR ChiTaRS; HTRA2; human.
DR EvolutionaryTrace; O43464; -.
DR GeneWiki; HtrA_serine_peptidase_2; -.
DR GenomeRNAi; 27429; -.
DR Pharos; O43464; Tbio.
DR PRO; PR:O43464; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; O43464; protein.
DR Bgee; ENSG00000115317; Expressed in cortical plate and 197 other tissues.
DR ExpressionAtlas; O43464; baseline and differential.
DR Genevisible; O43464; HS.
DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL.
DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL.
DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005783; C:endoplasmic reticulum; NAS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:MGI.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:1905370; C:serine-type endopeptidase complex; IMP:CAFA.
DR GO; GO:0042802; F:identical protein binding; IPI:CAFA.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB.
DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IMP:UniProtKB.
DR GO; GO:0034605; P:cellular response to heat; IDA:UniProtKB.
DR GO; GO:0035458; P:cellular response to interferon-beta; IDA:ParkinsonsUK-UCL.
DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0071300; P:cellular response to retinoic acid; IDA:ParkinsonsUK-UCL.
DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl.
DR GO; GO:0097194; P:execution phase of apoptosis; TAS:UniProtKB.
DR GO; GO:0030900; P:forebrain development; IEA:Ensembl.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:ParkinsonsUK-UCL.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
DR GO; GO:0045786; P:negative regulation of cell cycle; TAS:UniProtKB.
DR GO; GO:1904924; P:negative regulation of mitophagy in response to mitochondrial depolarization; IEA:Ensembl.
DR GO; GO:1901215; P:negative regulation of neuron death; TAS:ParkinsonsUK-UCL.
DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; NAS:ParkinsonsUK-UCL.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
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; IDA:UniProtKB.
DR GO; GO:2001269; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IMP:ParkinsonsUK-UCL.
DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB.
DR GO; GO:0010822; P:positive regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL.
DR GO; GO:0012501; P:programmed cell death; IDA:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; TAS:ParkinsonsUK-UCL.
DR GO; GO:0030163; P:protein catabolic process; IDA:ParkinsonsUK-UCL.
DR GO; GO:0006508; P:proteolysis; IDA:ParkinsonsUK-UCL.
DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR DisProt; DP00315; -.
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 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage;
KW Direct protein sequencing; Disease variant; Endoplasmic reticulum;
KW Epilepsy; Hydrolase; Membrane; Mitochondrion; Neurodegeneration;
KW Parkinson disease; Parkinsonism; Protease; Reference proteome;
KW Serine protease; Transit peptide; Transmembrane; Transmembrane helix;
KW Zymogen.
FT TRANSIT 1..31
FT /note="Mitochondrion"
FT PROPEP 32..133
FT /evidence="ECO:0000269|PubMed:11583623"
FT /id="PRO_0000026945"
FT CHAIN 134..458
FT /note="Serine protease HTRA2, mitochondrial"
FT /id="PRO_0000026946"
FT TRANSMEM 105..125
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 364..445
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 ACT_SITE 198
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:11967569"
FT ACT_SITE 228
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:11967569"
FT ACT_SITE 306
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:11967569"
FT VAR_SEQ 238..302
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10995577"
FT /id="VSP_005359"
FT VAR_SEQ 313
FT /note="L -> LARELGAVSLQ (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10971580"
FT /id="VSP_005360"
FT VAR_SEQ 314..458
FT /note="DGEVIGVNTMKVTAGISFAIPSDRLREFLHRGEKKNSSSGISGSQRRYIGVM
FT MLTLSPSILAELQLREPSFPDVQHGVLIHKVILGSPAHRAGLRPGDVILAIGEQMVQNA
FT EDVYEAVRTQSQLAVQIRRGRETLTLYVTPEVTE -> VSETSFLPRIPAPGQCGKGRF
FT PLIQGCLVKFLSSSLLAISQYPTRSPQHLLVLLFGCPHPLLFV (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:10971580"
FT /id="VSP_005362"
FT VAR_SEQ 372..403
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10971580,
FT ECO:0000303|PubMed:10995577"
FT /id="VSP_005361"
FT VARIANT 12
FT /note="W -> C (in dbSNP:rs775840965)"
FT /evidence="ECO:0000269|PubMed:18364387"
FT /id="VAR_076967"
FT VARIANT 72
FT /note="L -> P (in dbSNP:rs150047108)"
FT /evidence="ECO:0000269|PubMed:18401856"
FT /id="VAR_046134"
FT VARIANT 128
FT /note="P -> L (in dbSNP:rs757704467)"
FT /evidence="ECO:0000269|PubMed:18364387"
FT /id="VAR_076968"
FT VARIANT 141
FT /note="A -> S (may be a risk factor for Parkinson disease;
FT reduced protease activity; dbSNP:rs72470544)"
FT /evidence="ECO:0000269|PubMed:15961413,
FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:18401856"
FT /id="VAR_027349"
FT VARIANT 227
FT /note="A -> S (in dbSNP:rs375322953)"
FT /evidence="ECO:0000269|PubMed:18364387"
FT /id="VAR_076969"
FT VARIANT 243..244
FT /note="LP -> PS (in MGCA8; loss of protein expression;
FT dbSNP:rs1057519082)"
FT /evidence="ECO:0000269|PubMed:27696117"
FT /id="VAR_077960"
FT VARIANT 399
FT /note="G -> S (may be a risk factor for Parkinson disease;
FT reduced protease activity; dbSNP:rs72470545)"
FT /evidence="ECO:0000269|PubMed:15961413,
FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:25422467,
FT ECO:0000269|PubMed:27535533"
FT /id="VAR_027350"
FT VARIANT 404
FT /note="R -> Q (in MGCA8; may lead to skipping of exon 7 and
FT the resultant protein may be truncated; loss of protein
FT expression in patient cells homozygous for the mutation;
FT dbSNP:rs767006508)"
FT /evidence="ECO:0000269|PubMed:27208207"
FT /id="VAR_077961"
FT VARIANT 404
FT /note="R -> W (in PARK13; dbSNP:rs1380794702)"
FT /evidence="ECO:0000269|PubMed:18401856"
FT /id="VAR_046135"
FT MUTAGEN 134
FT /note="A->M: Loss of interaction with XIAP. Loss of
FT inhibition of XIAP activity."
FT /evidence="ECO:0000269|PubMed:11583623"
FT MUTAGEN 306
FT /note="S->A: Loss of protease activity."
FT /evidence="ECO:0000269|PubMed:10644717"
FT HELIX 143..147
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 149..157
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 158..160
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 161..170
FT /evidence="ECO:0007829|PDB:5M3N"
FT TURN 171..174
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 175..188
FT /evidence="ECO:0007829|PDB:5M3N"
FT TURN 189..191
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 192..195
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 198..200
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 204..209
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 211..213
FT /evidence="ECO:0007829|PDB:5TO0"
FT STRAND 215..224
FT /evidence="ECO:0007829|PDB:5M3N"
FT TURN 225..228
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 229..233
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 248..250
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 256..259
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 265..268
FT /evidence="ECO:0007829|PDB:5FHT"
FT STRAND 271..275
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 295..299
FT /evidence="ECO:0007829|PDB:5M3N"
FT TURN 303..307
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 308..311
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 317..326
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 329..334
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 335..342
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 359..361
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 364..368
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 371..380
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 382..384
FT /evidence="ECO:0007829|PDB:5WYN"
FT STRAND 391..396
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 401..405
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 412..416
FT /evidence="ECO:0007829|PDB:5M3N"
FT HELIX 424..433
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 435..443
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 446..452
FT /evidence="ECO:0007829|PDB:5M3N"
FT STRAND 455..457
FT /evidence="ECO:0007829|PDB:5M3N"
SQ SEQUENCE 458 AA; 48841 MW; CEA955A7D0DD8C0D CRC64;
MAAPRAGRGA GWSLRAWRAL GGIRWGRRPR LTPDLRALLT SGTSDPRARV TYGTPSLWAR
LSVGVTEPRA CLTSGTPGPR AQLTAVTPDT RTREASENSG TRSRAWLAVA LGAGGAVLLL
LWGGGRGPPA VLAAVPSPPP ASPRSQYNFI ADVVEKTAPA VVYIEILDRH PFLGREVPIS
NGSGFVVAAD GLIVTNAHVV ADRRRVRVRL LSGDTYEAVV TAVDPVADIA TLRIQTKEPL
PTLPLGRSAD VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQT NVEYIQTDAA
IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS SSGISGSQRR
YIGVMMLTLS PSILAELQLR EPSFPDVQHG VLIHKVILGS PAHRAGLRPG DVILAIGEQM
VQNAEDVYEA VRTQSQLAVQ IRRGRETLTL YVTPEVTE
