M3K5_HUMAN
ID M3K5_HUMAN Reviewed; 1374 AA.
AC Q99683; A6NIA0; B4DGB2; Q5THN3; Q99461;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 221.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 5;
DE EC=2.7.11.25 {ECO:0000269|PubMed:26095851};
DE AltName: Full=Apoptosis signal-regulating kinase 1;
DE Short=ASK-1;
DE AltName: Full=MAPK/ERK kinase kinase 5;
DE Short=MEK kinase 5;
DE Short=MEKK 5;
GN Name=MAP3K5; Synonyms=ASK1, MAPKKK5, MEKK5;
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), AND FUNCTION.
RX PubMed=8940179; DOI=10.1074/jbc.271.49.31607;
RA Wang X.S., Diener K., Jannuzzi D., Trollinger D., Tan T.-H.,
RA Lichenstein H., Zukowski M., Yao Z.;
RT "Molecular cloning and characterization of a novel protein kinase with a
RT catalytic domain homologous to mitogen-activated protein kinase kinase
RT kinase.";
RL J. Biol. Chem. 271:31607-31611(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=8974401; DOI=10.1126/science.275.5296.90;
RA Ichijo H., Nishida E., Irie K., ten Dijke P., Saitoh M., Moriguchi T.,
RA Takagi M., Matsumoto K., Miyazono K., Gotoh Y.;
RT "Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK
RT and p38 signaling pathways.";
RL Science 275:90-94(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Amygdala;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye, and Lung;
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 INTERACTION WITH TXN, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=9564042; DOI=10.1093/emboj/17.9.2596;
RA Saitoh M., Nishitoh H., Fujii M., Takeda K., Tobiume K., Sawada Y.,
RA Kawabata M., Miyazono K., Ichijo H.;
RT "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating
RT kinase (ASK) 1.";
RL EMBO J. 17:2596-2606(1998).
RN [7]
RP ACTIVITY REGULATION, INTERACTION WITH TRAF2, AND FUNCTION.
RX PubMed=9774977; DOI=10.1016/s1097-2765(00)80283-x;
RA Nishitoh H., Saitoh M., Mochida Y., Takeda K., Nakano H., Rothe M.,
RA Miyazono K., Ichijo H.;
RT "ASK1 is essential for JNK/SAPK activation by TRAF2.";
RL Mol. Cell 2:389-395(1998).
RN [8]
RP INTERACTION WITH DAXX, AND MUTAGENESIS OF LYS-709.
RX PubMed=9743501; DOI=10.1126/science.281.5384.1860;
RA Chang H.Y., Nishitoh H., Yang X., Ichijo H., Baltimore D.;
RT "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter
RT protein Daxx.";
RL Science 281:1860-1863(1998).
RN [9]
RP INTERACTION WITH 14-3-3 PROTEINS, ACTIVITY REGULATION, MUTAGENESIS OF
RP SER-966, AND FUNCTION.
RX PubMed=10411906; DOI=10.1073/pnas.96.15.8511;
RA Zhang L., Chen J., Fu H.;
RT "Suppression of apoptosis signal-regulating kinase 1-induced cell death by
RT 14-3-3 proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:8511-8515(1999).
RN [10]
RP FUNCTION IN APOPTOSIS.
RX PubMed=10849426; DOI=10.1074/jbc.m003412200;
RA Hatai T., Matsuzawa A., Inoshita S., Mochida Y., Kuroda T., Sakamaki K.,
RA Kuida K., Yonehara S., Ichijo H., Takeda K.;
RT "Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis
RT by the mitochondria-dependent caspase activation.";
RL J. Biol. Chem. 275:26576-26581(2000).
RN [11]
RP SUBUNIT, INTERACTION WITH TRAF2, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=10688666; DOI=10.1128/mcb.20.6.2198-2208.2000;
RA Liu H., Nishitoh H., Ichijo H., Kyriakis J.M.;
RT "Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor
RT necrosis factor receptor-associated factor 2 requires prior dissociation of
RT the ASK1 inhibitor thioredoxin.";
RL Mol. Cell. Biol. 20:2198-2208(2000).
RN [12]
RP INTERACTION WITH ARRB2.
RX PubMed=11090355; DOI=10.1126/science.290.5496.1574;
RA McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T.,
RA Davis R.J., Lefkowitz R.J.;
RT "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of
RT JNK3.";
RL Science 290:1574-1577(2000).
RN [13]
RP INTERACTION WITH PPP5C, DEPHOSPHORYLATION AT THR-838, SUBCELLULAR LOCATION,
RP ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=11689443; DOI=10.1093/emboj/20.21.6028;
RA Morita K., Saitoh M., Tobiume K., Matsuura H., Enomoto S., Nishitoh H.,
RA Ichijo H.;
RT "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in
RT response to oxidative stress.";
RL EMBO J. 20:6028-6036(2001).
RN [14]
RP FUNCTION IN KERATINOCYTE DIFFERENTIATION.
RX PubMed=11029458; DOI=10.1074/jbc.m003425200;
RA Sayama K., Hanakawa Y., Shirakata Y., Yamasaki K., Sawada Y., Sun L.,
RA Yamanishi K., Ichijo H., Hashimoto K.;
RT "Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of
RT keratinocyte differentiation.";
RL J. Biol. Chem. 276:999-1004(2001).
RN [15]
RP PHOSPHORYLATION AT SER-83, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=11154276; DOI=10.1128/mcb.21.3.893-901.2001;
RA Kim A.H., Khursigara G., Sun X., Franke T.F., Chao M.V.;
RT "Akt phosphorylates and negatively regulates apoptosis signal-regulating
RT kinase 1.";
RL Mol. Cell. Biol. 21:893-901(2001).
RN [16]
RP INTERACTION WITH HIV-1 NEF (MICROBIAL INFECTION), AND INHIBITION BY HIV-1
RP NEF (MICROBIAL INFECTION).
RX PubMed=11298454; DOI=10.1038/35071111;
RA Geleziunas R., Xu W., Takeda K., Ichijo H., Greene W.C.;
RT "HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential
RT mechanism for protecting the infected host cell.";
RL Nature 410:834-838(2001).
RN [17]
RP INTERACTION WITH RAF1.
RX PubMed=11427728; DOI=10.1073/pnas.141224398;
RA Chen J., Fujii K., Zhang L., Roberts T., Fu H.;
RT "Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating
RT kinase 1 through a MEK-ERK independent mechanism.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:7783-7788(2001).
RN [18]
RP INTERACTION WITH TRAF2 AND ERN1, ACTIVITY REGULATION, AND FUNCTION IN ER
RP STRESS RESPONSE.
RX PubMed=14749717; DOI=10.1038/sj.embor.7400072;
RA Takeda K., Matsuzawa A., Nishitoh H., Tobiume K., Kishida S.,
RA Ninomiya-Tsuji J., Matsumoto K., Ichijo H.;
RT "Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation.";
RL EMBO Rep. 5:161-166(2004).
RN [19]
RP FUNCTION, HOMODIMERIZATION, ACTIVITY REGULATION, AND PHOSPHORYLATION AT
RP THR-838.
RX PubMed=11920685; DOI=10.1002/jcp.10080;
RA Tobiume K., Saitoh M., Ichijo H.;
RT "Activation of apoptosis signal-regulating kinase 1 by the stress-induced
RT activating phosphorylation of pre-formed oligomer.";
RL J. Cell. Physiol. 191:95-104(2002).
RN [20]
RP INTERACTION WITH IGF1R, PHOSPHORYLATION, ACTIVITY REGULATION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=12556535; DOI=10.1074/jbc.m211398200;
RA Galvan V., Logvinova A., Sperandio S., Ichijo H., Bredesen D.E.;
RT "Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits
RT apoptosis signal-regulating kinase 1 (ASK1).";
RL J. Biol. Chem. 278:13325-13332(2003).
RN [21]
RP RETRACTED PAPER.
RX PubMed=12697749; DOI=10.1074/jbc.m302674200;
RA Yuan Z.Q., Feldman R.I., Sussman G.E., Coppola D., Nicosia S.V.,
RA Cheng J.Q.;
RT "AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by
RT phosphorylation of ASK1: implication of AKT2 in chemoresistance.";
RL J. Biol. Chem. 278:23432-23440(2003).
RN [22]
RP RETRACTION NOTICE OF PUBMED:12697749.
RX PubMed=27825085; DOI=10.1074/jbc.a116.302674;
RA Yuan Z.Q., Feldman R.I., Sussman G.E., Coppola D., Nicosia S.V.,
RA Cheng J.Q.;
RL J. Biol. Chem. 291:22847-22847(2016).
RN [23]
RP INTERACTION WITH DAB2IP.
RX PubMed=12813029; DOI=10.1172/jci200317790;
RA Zhang R., He X., Liu W., Lu M., Hsieh J.-T., Min W.;
RT "AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating
RT dissociation of ASK1 from its inhibitor 14-3-3.";
RL J. Clin. Invest. 111:1933-1943(2003).
RN [24]
RP INTERACTION WITH YWHAB; YWHAE; YWHAH; YWHAQ; YWHAZ AND SFN, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=15023544; DOI=10.1016/j.yexcr.2003.12.009;
RA Subramanian R.R., Zhang H., Wang H., Ichijo H., Miyashita T., Fu H.;
RT "Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-
RT 3 proteins.";
RL Exp. Cell Res. 294:581-591(2004).
RN [25]
RP PHOSPHORYLATION AT SER-966, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=14688258; DOI=10.1074/jbc.m311129200;
RA Goldman E.H., Chen L., Fu H.;
RT "Activation of apoptosis signal-regulating kinase 1 by reactive oxygen
RT species through dephosphorylation at serine 967 and 14-3-3 dissociation.";
RL J. Biol. Chem. 279:10442-10449(2004).
RN [26]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.m407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [27]
RP ACTIVITY REGULATION, PHOSPHORYLATION AT SER-966 AND SER-1033, MUTAGENESIS
RP OF SER-966 AND SER-1033, AND INTERACTION WITH YWHAG.
RX PubMed=15094778; DOI=10.1038/sj.onc.1207668;
RA Fujii K., Goldman E.H., Park H.R., Zhang L., Chen J., Fu H.;
RT "Negative control of apoptosis signal-regulating kinase 1 through
RT phosphorylation of Ser-1034.";
RL Oncogene 23:5099-5104(2004).
RN [28]
RP INTERACTION WITH STUB1, AND UBIQUITINATION.
RX PubMed=16038411; DOI=10.1379/csc-90r.1;
RA Hwang J.R., Zhang C., Patterson C.;
RT "C-terminus of heat shock protein 70-interacting protein facilitates
RT degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis
RT signal-regulating kinase 1-dependent apoptosis.";
RL Cell Stress Chaperones 10:147-156(2005).
RN [29]
RP INTERACTION WITH HIPK1, AND SUBCELLULAR LOCATION.
RX PubMed=15701637; DOI=10.1074/jbc.m414262200;
RA Li X., Zhang R., Luo D., Park S.-J., Wang Q., Kim Y., Min W.;
RT "Tumor necrosis factor alpha-induced desumoylation and cytoplasmic
RT translocation of homeodomain-interacting protein kinase 1 are critical for
RT apoptosis signal-regulating kinase 1-JNK/p38 activation.";
RL J. Biol. Chem. 280:15061-15070(2005).
RN [30]
RP SUBUNIT, INTERACTION WITH TRAF2, AND FUNCTION.
RX PubMed=16129676; DOI=10.1074/jbc.m506771200;
RA Noguchi T., Takeda K., Matsuzawa A., Saegusa K., Nakano H., Gohda J.,
RA Inoue J., Ichijo H.;
RT "Recruitment of tumor necrosis factor receptor-associated factor family
RT proteins to apoptosis signal-regulating kinase 1 signalosome is essential
RT for oxidative stress-induced cell death.";
RL J. Biol. Chem. 280:37033-37040(2005).
RN [31]
RP PHOSPHORYLATION AT TYR-718, INTERACTION WITH SOCS1, AND ACTIVITY
RP REGULATION.
RX PubMed=16407264; DOI=10.1074/jbc.m512338200;
RA He Y., Zhang W., Zhang R., Zhang H., Min W.;
RT "SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK
RT inflammatory signaling by mediating ASK1 degradation.";
RL J. Biol. Chem. 281:5559-5566(2006).
RN [32]
RP INTERACTION WITH PPM1L.
RX PubMed=17456047; DOI=10.1042/bj20070231;
RA Saito J., Toriumi S., Awano K., Ichijo H., Sasaki K., Kobayashi T.,
RA Tamura S.;
RT "Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase
RT 2Cepsilon.";
RL Biochem. J. 405:591-596(2007).
RN [33]
RP ACTIVITY REGULATION, INTERACTION WITH MAP3K5, PHOSPHORYLATION AT THR-838,
RP AND MUTAGENESIS OF LYS-709.
RX PubMed=17210579; DOI=10.1074/jbc.m607177200;
RA Takeda K., Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I.,
RA Tobiume K., Saitoh M., Matsuzawa A., Ichijo H.;
RT "Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-
RT activated protein kinase kinase kinase in a heteromeric complex with
RT ASK1.";
RL J. Biol. Chem. 282:7522-7531(2007).
RN [34]
RP INTERACTION WITH BIRC2, UBIQUITINATION, AND FUNCTION.
RX PubMed=17220297; DOI=10.1074/jbc.m609146200;
RA Zhao Y., Conze D.B., Hanover J.A., Ashwell J.D.;
RT "Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-
RT dependent ASK1 ubiquitination and terminates mitogen-activated protein
RT kinase signaling.";
RL J. Biol. Chem. 282:7777-7782(2007).
RN [35]
RP INTERACTION WITH DAB2IP.
RX PubMed=17389591; DOI=10.1074/jbc.m701148200;
RA Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.;
RT "RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical
RT for tumor necrosis factor-induced ASK1-JNK/p38 activation.";
RL J. Biol. Chem. 282:14788-14796(2007).
RN [36]
RP INTERACTION WITH TRAF2; TRAF6 AND TXN.
RX PubMed=17724081; DOI=10.1128/mcb.00227-07;
RA Fujino G., Noguchi T., Matsuzawa A., Yamauchi S., Saitoh M., Takeda K.,
RA Ichijo H.;
RT "Thioredoxin and TRAF family proteins regulate reactive oxygen species-
RT dependent activation of ASK1 through reciprocal modulation of the N-
RT terminal homophilic interaction of ASK1.";
RL Mol. Cell. Biol. 27:8152-8163(2007).
RN [37]
RP INTERACTION WITH ARRB2.
RX PubMed=18408005; DOI=10.1074/jbc.m710006200;
RA Guo C., Whitmarsh A.J.;
RT "The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3
RT activation by binding to its nonconserved N terminus.";
RL J. Biol. Chem. 283:15903-15911(2008).
RN [38]
RP PHOSPHORYLATION AT THR-838.
RX PubMed=18948261; DOI=10.1074/jbc.m807219200;
RA Jung H., Seong H.A., Ha H.;
RT "Murine protein serine/threonine kinase 38 activates apoptosis signal-
RT regulating kinase 1 via Thr 838 phosphorylation.";
RL J. Biol. Chem. 283:34541-34553(2008).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1029 AND SER-1033, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1029 AND SER-1033, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [41]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1033, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [42]
RP PHOSPHORYLATION AT SER-83 BY PIM1, AND INTERACTION WITH PIM1.
RX PubMed=19749799; DOI=10.1038/onc.2009.276;
RA Gu J.J., Wang Z., Reeves R., Magnuson N.S.;
RT "PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis.";
RL Oncogene 28:4261-4271(2009).
RN [43]
RP INTERACTION WITH PGAM5, AND PHOSPHORYLATION AT THR-838; SER-966 AND
RP SER-1033.
RX PubMed=19590015; DOI=10.1073/pnas.0901823106;
RA Takeda K., Komuro Y., Hayakawa T., Oguchi H., Ishida Y., Murakami S.,
RA Noguchi T., Kinoshita H., Sekine Y., Iemura S., Natsume T., Ichijo H.;
RT "Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity
RT as a protein serine/threonine phosphatase to activate ASK1.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:12301-12305(2009).
RN [44]
RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=17883330; DOI=10.1146/annurev.pharmtox.48.113006.094606;
RA Takeda K., Noguchi T., Naguro I., Ichijo H.;
RT "Apoptosis signal-regulating kinase 1 in stress and immune response.";
RL Annu. Rev. Pharmacol. Toxicol. 48:199-225(2008).
RN [45]
RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=19389260; DOI=10.1186/1478-811x-7-9;
RA Hattori K., Naguro I., Runchel C., Ichijo H.;
RT "The roles of ASK family proteins in stress responses and diseases.";
RL Cell Commun. Signal. 7:9-9(2009).
RN [46]
RP INTERACTION WITH DUSP13.
RX PubMed=20358250; DOI=10.1007/s00018-010-0353-3;
RA Park J.E., Park B.C., Kim H.A., Song M., Park S.G., Lee D.H., Kim H.J.,
RA Choi H.K., Kim J.T., Cho S.;
RT "Positive regulation of apoptosis signal-regulating kinase 1 by dual-
RT specificity phosphatase 13A.";
RL Cell. Mol. Life Sci. 67:2619-2629(2010).
RN [47]
RP INTERACTION WITH PRMT1 AND TRAF2, METHYLATION AT ARG-78 AND ARG-80, AND
RP MUTAGENESIS OF ARG-32; ARG-78 AND ARG-80.
RX PubMed=22095282; DOI=10.1038/cdd.2011.168;
RA Cho J.H., Lee M.K., Yoon K.W., Lee J., Cho S.G., Choi E.J.;
RT "Arginine methylation-dependent regulation of ASK1 signaling by PRMT1.";
RL Cell Death Differ. 19:859-870(2012).
RN [48]
RP FUNCTION, PHOSPHORYLATION AT THR-838, AND DEPHOSPHORYLATION AT THR-838 BY
RP PPP5C.
RX PubMed=23102700; DOI=10.1016/j.molcel.2012.09.018;
RA Sekine Y., Hatanaka R., Watanabe T., Sono N., Iemura S., Natsume T.,
RA Kuranaga E., Miura M., Takeda K., Ichijo H.;
RT "The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1
RT activation by suppressing PP5.";
RL Mol. Cell 48:692-704(2012).
RN [49]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-958, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [50]
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 [51]
RP INTERACTION WITH RC3H2, AND MUTAGENESIS OF LYS-709.
RX PubMed=24448648; DOI=10.1126/scisignal.2004822;
RA Maruyama T., Araki T., Kawarazaki Y., Naguro I., Heynen S., Aza-Blanc P.,
RA Ronai Z., Matsuzawa A., Ichijo H.;
RT "Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate
RT stress responses.";
RL Sci. Signal. 7:RA8-RA8(2014).
RN [52]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP PHOSPHORYLATION AT SER-966, AND INTERACTION WITH PPIA.
RX PubMed=26095851; DOI=10.1016/j.bbrc.2015.06.078;
RA Kim H., Oh Y., Kim K., Jeong S., Chon S., Kim D., Jung M.H., Pak Y.K.,
RA Ha J., Kang I., Choe W.;
RT "Cyclophilin A regulates JNK/p38-MAPK signaling through its physical
RT interaction with ASK1.";
RL Biochem. Biophys. Res. Commun. 464:112-117(2015).
RN [53]
RP INTERACTION WITH TRIM48, METHYLATION, UBIQUITINATION, AND MUTAGENESIS OF
RP LYS-709 AND THR-838.
RX PubMed=29186683; DOI=10.1016/j.celrep.2017.11.007;
RA Hirata Y., Katagiri K., Nagaoka K., Morishita T., Kudoh Y., Hatta T.,
RA Naguro I., Kano K., Udagawa T., Natsume T., Aoki J., Inada T., Noguchi T.,
RA Ichijo H., Matsuzawa A.;
RT "TRIM48 Promotes ASK1 Activation and Cell Death through Ubiquitination-
RT Dependent Degradation of the ASK1-Negative Regulator PRMT1.";
RL Cell Rep. 21:2447-2457(2017).
RN [54]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 659-951, AND PHOSPHORYLATION AT
RP THR-813; THR-838 AND THR-842.
RX PubMed=17937911; DOI=10.1016/j.str.2007.08.011;
RA Bunkoczi G., Salah E., Filippakopoulos P., Fedorov O., Muller S.,
RA Sobott F., Parker S.A., Zhang H., Min W., Turk B.E., Knapp S.;
RT "Structural and functional characterization of the human protein kinase
RT ASK1.";
RL Structure 15:1215-1226(2007).
RN [55]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-1006; THR-1214; VAL-1250; ILE-1314 AND
RP ASN-1315.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential component
CC of the MAP kinase signal transduction pathway. Plays an important role
CC in the cascades of cellular responses evoked by changes in the
CC environment. Mediates signaling for determination of cell fate such as
CC differentiation and survival. Plays a crucial role in the apoptosis
CC signal transduction pathway through mitochondria-dependent caspase
CC activation. MAP3K5/ASK1 is required for the innate immune response,
CC which is essential for host defense against a wide range of pathogens.
CC Mediates signal transduction of various stressors like oxidative stress
CC as well as by receptor-mediated inflammatory signals, such as the tumor
CC necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts
CC as an upstream activator of the MKK/JNK signal transduction cascade and
CC the p38 MAPK signal transduction cascade through the phosphorylation
CC and activation of several MAP kinase kinases like MAP2K4/SEK1,
CC MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate
CC p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs
CC control the transcription factors activator protein-1 (AP-1).
CC {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666,
CC ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458,
CC ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443,
CC ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:14688258,
CC ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544,
CC ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297,
CC ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:26095851,
CC ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401,
CC ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC Evidence={ECO:0000269|PubMed:26095851};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25; Evidence={ECO:0000269|PubMed:26095851};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated by various stressors, including
CC oxidative stress, endoplasmic reticulum stress, and calcium overload,
CC as well as by receptor-mediated inflammatory signals, such as the tumor
CC necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic
CC association of MAP3K5/ASK1 through the C-terminal coiled-coil domains
CC and the heteromeric complex formation of MAP3K5/ASK1 with the reduced
CC form of thioredoxin (TXN), constitutes an inactive form of the kinase
CC (PubMed:17210579, PubMed:9564042). Upon ROS-induced dissociation of TXN
CC from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to
CC MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2
CC and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1
CC (PubMed:9774977, PubMed:10688666, PubMed:11920685). MAP3K5/ASK1
CC activity is also regulated through several phosphorylation and
CC dephosphorylation events. Thr-838 is an activating phosphorylation site
CC that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and
CC dephosphorylated by PPP5C (PubMed:11689443). Ser-83 and Ser-1033 are
CC inactivating phosphorylation sites, the former of which is
CC phosphorylated by AKT1 (PubMed:11154276, PubMed:15094778).
CC Phosphorylation of Ser-966 induces association of MAP3K5/ASK1 with the
CC 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity
CC (PubMed:10411906, PubMed:14688258). Calcium/calmodulin-activated
CC protein phosphatase calcineurin (PPP3CA) has been shown to directly
CC dephosphorylate this site (PubMed:14749717). SOCS1 binds to ASK1 by
CC recognizing phosphorylation of Tyr-718 and induces MAP3K5/ASK1
CC degradation in endothelial cells (PubMed:16407264). Also
CC dephosphorylated and activated by PGAM5. Contains an N-terminal
CC autoinhibitory domain. Once activated targeted for proteosomal
CC degradation by RC3H2-mediated ubiquitination (PubMed:24448648).
CC {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666,
CC ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443,
CC ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12556535,
CC ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717,
CC ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264,
CC ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:24448648,
CC ECO:0000269|PubMed:26095851, ECO:0000269|PubMed:9564042,
CC ECO:0000269|PubMed:9774977}.
CC -!- SUBUNIT: Homodimer when inactive. Binds both upstream activators and
CC downstream substrates in multimolecular complexes. Part of a
CC cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF
CC (PubMed:15310755, PubMed:15701637, PubMed:17210579, PubMed:17389591).
CC This complex formation promotes MAP3K5-JNK activation and subsequent
CC apoptosis. Interacts with SOCS1 which recognizes phosphorylation of
CC Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells.
CC Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ,
CC YWHAH, YWHAZ and SFN (PubMed:10411906, PubMed:15023544,
CC PubMed:15094778). Interacts with ARRB2, BIRC2, DAB2IP, IGF1R,
CC MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN
CC (PubMed:9564042,PubMed:9774977, PubMed:10688666, PubMed:11090355,
CC PubMed:11689443, PubMed:12556535, PubMed:12813029, PubMed:15310755,
CC PubMed:16038411, PubMed:16129676, PubMed:16407264, PubMed:17220297,
CC PubMed:17724081, PubMed:18408005, PubMed:19590015, PubMed:19749799).
CC Interacts with ERN1 in a TRAF2-dependent manner (PubMed:14749717).
CC Interacts with calcineurin subunit PPP3R1 (By similarity). Interacts
CC with PPM1L (PubMed:17456047). Interacts (via N-terminus) with RAF1 and
CC this interaction inhibits the proapoptotic function of MAP3K5
CC (PubMed:11427728). Interacts with DAB2IP (via N-terminus C2 domain);
CC the interaction occurs in a TNF-alpha-dependent manner
CC (PubMed:15310755). Interacts with DUSP13/DUSP13A; may positively
CC regulate apoptosis (PubMed:20358250). Interacts with DAXX
CC (PubMed:9743501). Interacts with RC3H2 (PubMed:24448648). Interacts
CC with PPIA/CYPA (PubMed:26095851). Interacts with PRMT1; the interaction
CC results in MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation
CC (PubMed:22095282). Interacts with TRAF2; the interaction is inhibited
CC by PRMT1 (PubMed:22095282). Interacts with TRIM48 (PubMed:29186683).
CC {ECO:0000250|UniProtKB:O35099, ECO:0000269|PubMed:10411906,
CC ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:11090355,
CC ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11689443,
CC ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:12813029,
CC ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544,
CC ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:15310755,
CC ECO:0000269|PubMed:15701637, ECO:0000269|PubMed:16038411,
CC ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:16407264,
CC ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17220297,
CC ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:17456047,
CC ECO:0000269|PubMed:17724081, ECO:0000269|PubMed:18408005,
CC ECO:0000269|PubMed:19590015, ECO:0000269|PubMed:19749799,
CC ECO:0000269|PubMed:20358250, ECO:0000269|PubMed:22095282,
CC ECO:0000269|PubMed:24448648, ECO:0000269|PubMed:26095851,
CC ECO:0000269|PubMed:29186683, ECO:0000269|PubMed:9564042,
CC ECO:0000269|PubMed:9743501, ECO:0000269|PubMed:9774977}.
CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 Nef; this
CC interaction inhibits MAP3K5 signaling. {ECO:0000269|PubMed:11298454}.
CC -!- INTERACTION:
CC Q99683; P31749: AKT1; NbExp=2; IntAct=EBI-476263, EBI-296087;
CC Q99683; P49407: ARRB1; NbExp=3; IntAct=EBI-476263, EBI-743313;
CC Q99683; P32121: ARRB2; NbExp=2; IntAct=EBI-476263, EBI-714559;
CC Q99683; Q99828: CIB1; NbExp=7; IntAct=EBI-476263, EBI-372594;
CC Q99683; P02489: CRYAA; NbExp=3; IntAct=EBI-476263, EBI-6875961;
CC Q99683; Q5VWQ8: DAB2IP; NbExp=2; IntAct=EBI-476263, EBI-2871881;
CC Q99683; Q9UER7: DAXX; NbExp=7; IntAct=EBI-476263, EBI-77321;
CC Q99683; P50570-2: DNM2; NbExp=3; IntAct=EBI-476263, EBI-10968534;
CC Q99683; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-476263, EBI-356015;
CC Q99683; P20042: EIF2S2; NbExp=3; IntAct=EBI-476263, EBI-711977;
CC Q99683; P41091: EIF2S3; NbExp=3; IntAct=EBI-476263, EBI-1054228;
CC Q99683; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-476263, EBI-10226858;
CC Q99683; Q8TB36: GDAP1; NbExp=3; IntAct=EBI-476263, EBI-11110431;
CC Q99683; P28799: GRN; NbExp=3; IntAct=EBI-476263, EBI-747754;
CC Q99683; P54652: HSPA2; NbExp=3; IntAct=EBI-476263, EBI-356991;
CC Q99683; P04792: HSPB1; NbExp=3; IntAct=EBI-476263, EBI-352682;
CC Q99683; O43464: HTRA2; NbExp=3; IntAct=EBI-476263, EBI-517086;
CC Q99683; P42858: HTT; NbExp=6; IntAct=EBI-476263, EBI-466029;
CC Q99683; O60333-2: KIF1B; NbExp=3; IntAct=EBI-476263, EBI-10975473;
CC Q99683; Q92876: KLK6; NbExp=3; IntAct=EBI-476263, EBI-2432309;
CC Q99683; Q14114-3: LRP8; NbExp=3; IntAct=EBI-476263, EBI-25832196;
CC Q99683; P46734: MAP2K3; NbExp=6; IntAct=EBI-476263, EBI-602462;
CC Q99683; Q99683: MAP3K5; NbExp=5; IntAct=EBI-476263, EBI-476263;
CC Q99683; Q96EZ8: MCRS1; NbExp=3; IntAct=EBI-476263, EBI-348259;
CC Q99683; Q96HS1: PGAM5; NbExp=2; IntAct=EBI-476263, EBI-713608;
CC Q99683; P63098: PPP3R1; NbExp=2; IntAct=EBI-476263, EBI-915984;
CC Q99683; P60891: PRPS1; NbExp=3; IntAct=EBI-476263, EBI-749195;
CC Q99683; Q16637: SMN2; NbExp=3; IntAct=EBI-476263, EBI-395421;
CC Q99683; Q12933: TRAF2; NbExp=4; IntAct=EBI-476263, EBI-355744;
CC Q99683; P10599: TXN; NbExp=4; IntAct=EBI-476263, EBI-594644;
CC Q99683; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-476263, EBI-11141397;
CC Q99683; P31946: YWHAB; NbExp=3; IntAct=EBI-476263, EBI-359815;
CC Q99683; Q04917: YWHAH; NbExp=3; IntAct=EBI-476263, EBI-306940;
CC Q99683; P63104: YWHAZ; NbExp=4; IntAct=EBI-476263, EBI-347088;
CC Q99683; Q969S3: ZNF622; NbExp=14; IntAct=EBI-476263, EBI-2687480;
CC Q99683; Q9WTR2: Map3k6; Xeno; NbExp=3; IntAct=EBI-476263, EBI-1254790;
CC Q99683; Q9D1C8: Vps28; Xeno; NbExp=5; IntAct=EBI-476263, EBI-309205;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:26095851}.
CC Endoplasmic reticulum. Note=Interaction with 14-3-3 proteins alters the
CC distribution of MAP3K5/ASK1 and restricts it to the perinuclear
CC endoplasmic reticulum region.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q99683-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99683-2; Sequence=VSP_056182;
CC -!- TISSUE SPECIFICITY: Abundantly expressed in heart and pancreas.
CC -!- INDUCTION: By TNF. Inhibited by HIV-1 Nef.
CC -!- PTM: Phosphorylated at Thr-838 through autophosphorylation and by
CC MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by
CC PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the
CC former of which is phosphorylated by AKT1. Phosphorylated at Ser-966
CC which induces association of MAP3K5/ASK1 with the 14-3-3 family
CC proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN)
CC dephosphorylates this site. Also dephosphorylated and activated by
CC PGAM5. Phosphorylation at Ser-966 in response to oxidative stress is
CC negatively regulated by PPIA/CYPA (PubMed:26095851).
CC {ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11920685,
CC ECO:0000269|PubMed:12556535, ECO:0000269|PubMed:14688258,
CC ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:16407264,
CC ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17937911,
CC ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:19590015,
CC ECO:0000269|PubMed:19749799, ECO:0000269|PubMed:23102700,
CC ECO:0000269|PubMed:26095851}.
CC -!- PTM: Ubiquitinated (PubMed:16038411, PubMed:17220297, PubMed:29186683).
CC Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination,
CC leading to proteasomal degradation (PubMed:17220297). Ubiquitinated by
CC RC3H2 in a TRIM48-dependent manner (PubMed:29186683).
CC {ECO:0000269|PubMed:16038411, ECO:0000269|PubMed:17220297,
CC ECO:0000269|PubMed:29186683}.
CC -!- PTM: Methylation at Arg-78 and Arg-80 by PRMT1 promotes association of
CC MAP3K5 with thioredoxin and negatively regulates MAP3K5 association
CC with TRAF2, inhibiting MAP3K5 activation (PubMed:22095282). Methylation
CC is blocked by ubiquitination of PRMT1 by TRIM48 (PubMed:29186683).
CC {ECO:0000269|PubMed:22095282, ECO:0000269|PubMed:29186683}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: Reported to be phosphorylated by AKT2 (PubMed:12697749).
CC However, the publication has been retracted due to image duplication in
CC figures. {ECO:0000269|PubMed:12697749, ECO:0000305|PubMed:27825085}.
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DR EMBL; U67156; AAC50894.1; -; mRNA.
DR EMBL; D84476; BAA12684.2; -; mRNA.
DR EMBL; AK294507; BAG57723.1; -; mRNA.
DR EMBL; AL024508; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121933; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC054503; AAH54503.1; -; mRNA.
DR EMBL; BC088829; AAH88829.1; -; mRNA.
DR CCDS; CCDS5179.1; -. [Q99683-1]
DR RefSeq; NP_005914.1; NM_005923.3. [Q99683-1]
DR PDB; 2CLQ; X-ray; 2.30 A; A/B=659-951.
DR PDB; 3VW6; X-ray; 2.40 A; A/B=671-939.
DR PDB; 4BF2; X-ray; 2.11 A; A/B=660-977.
DR PDB; 4BHN; X-ray; 2.30 A; A/B=660-977.
DR PDB; 4BIB; X-ray; 2.43 A; A/B=660-977.
DR PDB; 4BIC; X-ray; 2.62 A; A/B=660-977.
DR PDB; 4BID; X-ray; 2.80 A; A/B=660-977.
DR PDB; 4BIE; X-ray; 2.36 A; A/B=660-977.
DR PDB; 5ULM; X-ray; 2.10 A; A/B=269-658.
DR PDB; 5UOR; X-ray; 2.75 A; A/B=670-939.
DR PDB; 5UOX; X-ray; 2.50 A; A/B=670-940.
DR PDB; 5UP3; X-ray; 2.95 A; A/B=670-940.
DR PDB; 5V19; X-ray; 3.10 A; A/B=670-940.
DR PDB; 5V24; X-ray; 2.50 A; A/B=670-940.
DR PDB; 5VIL; X-ray; 2.64 A; A/B/C/D=659-951.
DR PDB; 5VIO; X-ray; 2.84 A; A/B/C/D=659-951.
DR PDB; 6E2M; X-ray; 2.25 A; A/B=659-951.
DR PDB; 6E2N; X-ray; 2.10 A; A/B=659-951.
DR PDB; 6E2O; X-ray; 2.39 A; A/B=659-951.
DR PDB; 6EJL; X-ray; 2.38 A; C/D=963-970.
DR PDB; 6OYT; X-ray; 2.82 A; A/B/C/D=667-939.
DR PDB; 6OYW; X-ray; 2.60 A; A/B/C/D=658-951.
DR PDB; 6VRE; X-ray; 2.29 A; A/B=661-951.
DR PDB; 6XIH; X-ray; 2.65 A; A/B=667-953.
DR PDBsum; 2CLQ; -.
DR PDBsum; 3VW6; -.
DR PDBsum; 4BF2; -.
DR PDBsum; 4BHN; -.
DR PDBsum; 4BIB; -.
DR PDBsum; 4BIC; -.
DR PDBsum; 4BID; -.
DR PDBsum; 4BIE; -.
DR PDBsum; 5ULM; -.
DR PDBsum; 5UOR; -.
DR PDBsum; 5UOX; -.
DR PDBsum; 5UP3; -.
DR PDBsum; 5V19; -.
DR PDBsum; 5V24; -.
DR PDBsum; 5VIL; -.
DR PDBsum; 5VIO; -.
DR PDBsum; 6E2M; -.
DR PDBsum; 6E2N; -.
DR PDBsum; 6E2O; -.
DR PDBsum; 6EJL; -.
DR PDBsum; 6OYT; -.
DR PDBsum; 6OYW; -.
DR PDBsum; 6VRE; -.
DR PDBsum; 6XIH; -.
DR AlphaFoldDB; Q99683; -.
DR SMR; Q99683; -.
DR BioGRID; 110381; 131.
DR CORUM; Q99683; -.
DR DIP; DIP-29516N; -.
DR ELM; Q99683; -.
DR IntAct; Q99683; 65.
DR MINT; Q99683; -.
DR STRING; 9606.ENSP00000351908; -.
DR BindingDB; Q99683; -.
DR ChEMBL; CHEMBL5285; -.
DR GuidetoPHARMACOLOGY; 2080; -.
DR CarbonylDB; Q99683; -.
DR iPTMnet; Q99683; -.
DR PhosphoSitePlus; Q99683; -.
DR BioMuta; MAP3K5; -.
DR DMDM; 6685617; -.
DR CPTAC; CPTAC-849; -.
DR CPTAC; CPTAC-850; -.
DR EPD; Q99683; -.
DR jPOST; Q99683; -.
DR MassIVE; Q99683; -.
DR MaxQB; Q99683; -.
DR PaxDb; Q99683; -.
DR PeptideAtlas; Q99683; -.
DR PRIDE; Q99683; -.
DR ProteomicsDB; 1258; -.
DR ProteomicsDB; 78395; -. [Q99683-1]
DR Antibodypedia; 3592; 1586 antibodies from 44 providers.
DR DNASU; 4217; -.
DR Ensembl; ENST00000359015.5; ENSP00000351908.4; ENSG00000197442.10. [Q99683-1]
DR GeneID; 4217; -.
DR KEGG; hsa:4217; -.
DR MANE-Select; ENST00000359015.5; ENSP00000351908.4; NM_005923.4; NP_005914.1.
DR UCSC; uc003qhc.4; human. [Q99683-1]
DR CTD; 4217; -.
DR DisGeNET; 4217; -.
DR GeneCards; MAP3K5; -.
DR HGNC; HGNC:6857; MAP3K5.
DR HPA; ENSG00000197442; Tissue enhanced (adrenal).
DR MIM; 602448; gene.
DR neXtProt; NX_Q99683; -.
DR OpenTargets; ENSG00000197442; -.
DR PharmGKB; PA30601; -.
DR VEuPathDB; HostDB:ENSG00000197442; -.
DR eggNOG; KOG4279; Eukaryota.
DR GeneTree; ENSGT00940000159155; -.
DR HOGENOM; CLU_003687_1_0_1; -.
DR InParanoid; Q99683; -.
DR OMA; ETNSCHL; -.
DR OrthoDB; 226722at2759; -.
DR PhylomeDB; Q99683; -.
DR TreeFam; TF105115; -.
DR BRENDA; 2.7.12.2; 2681.
DR PathwayCommons; Q99683; -.
DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR SignaLink; Q99683; -.
DR SIGNOR; Q99683; -.
DR BioGRID-ORCS; 4217; 14 hits in 1116 CRISPR screens.
DR ChiTaRS; MAP3K5; human.
DR EvolutionaryTrace; Q99683; -.
DR GeneWiki; ASK1; -.
DR GenomeRNAi; 4217; -.
DR Pharos; Q99683; Tchem.
DR PRO; PR:Q99683; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q99683; protein.
DR Bgee; ENSG00000197442; Expressed in endothelial cell and 201 other tissues.
DR Genevisible; Q99683; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:1990604; C:IRE1-TRAF2-ASK1 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:1902911; C:protein kinase complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IDA:BHF-UCL.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; IPI:CAFA.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IDA:CAFA.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:BHF-UCL.
DR GO; GO:1902170; P:cellular response to reactive nitrogen species; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; TAS:Reactome.
DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:ParkinsonsUK-UCL.
DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IDA:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB.
DR GO; GO:0038066; P:p38MAPK cascade; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISS:ParkinsonsUK-UCL.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IMP:ParkinsonsUK-UCL.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IEA:Ensembl.
DR GO; GO:1901216; P:positive regulation of neuron death; IGI:ParkinsonsUK-UCL.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IEA:Ensembl.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:CAFA.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0097300; P:programmed necrotic cell death; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IDA:CAFA.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; IDA:CAFA.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR043969; MAP3K_PH.
DR InterPro; IPR025136; MAP3K_TRAF-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF19039; ASK_PH; 1.
DR Pfam; PF13281; MAP3K_TRAF_bd; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; ATP-binding; Coiled coil;
KW Cytoplasm; Endoplasmic reticulum; Host-virus interaction; Immunity;
KW Innate immunity; Kinase; Magnesium; Metal-binding; Methylation;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Ubl conjugation.
FT CHAIN 1..1374
FT /note="Mitogen-activated protein kinase kinase kinase 5"
FT /id="PRO_0000086249"
FT DOMAIN 680..938
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 68..87
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 649..1374
FT /note="Interaction with PPIA/CYPA"
FT /evidence="ECO:0000269|PubMed:26095851"
FT REGION 1182..1209
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 1245..1285
FT /evidence="ECO:0000255"
FT ACT_SITE 803
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 686..694
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 709
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 78
FT /note="Asymmetric dimethylarginine; by PRMT1"
FT /evidence="ECO:0000269|PubMed:22095282"
FT MOD_RES 80
FT /note="Asymmetric dimethylarginine; by PRMT1"
FT /evidence="ECO:0000269|PubMed:22095282"
FT MOD_RES 83
FT /note="Phosphoserine; by PIM1 and PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:11154276,
FT ECO:0000269|PubMed:19749799"
FT MOD_RES 718
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:16407264"
FT MOD_RES 813
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:17937911"
FT MOD_RES 838
FT /note="Phosphothreonine; by autocatalysis, MELK and MAP3K6"
FT /evidence="ECO:0000269|PubMed:11920685,
FT ECO:0000269|PubMed:17210579, ECO:0000269|PubMed:17937911,
FT ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:19590015,
FT ECO:0000269|PubMed:23102700"
FT MOD_RES 842
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:17937911"
FT MOD_RES 958
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 966
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14688258,
FT ECO:0000269|PubMed:15094778, ECO:0000269|PubMed:19590015,
FT ECO:0000269|PubMed:26095851"
FT MOD_RES 1029
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18088087,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 1033
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15094778,
FT ECO:0000269|PubMed:19590015, ECO:0007744|PubMed:18088087,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19369195"
FT VAR_SEQ 1..753
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056182"
FT VARIANT 1006
FT /note="G -> R (in dbSNP:rs45626535)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040693"
FT VARIANT 1214
FT /note="I -> T (in dbSNP:rs56379668)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040694"
FT VARIANT 1250
FT /note="I -> V (in dbSNP:rs35551087)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040695"
FT VARIANT 1314
FT /note="T -> I (in dbSNP:rs45599539)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040696"
FT VARIANT 1315
FT /note="D -> N (in dbSNP:rs41288957)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040697"
FT MUTAGEN 32
FT /note="R->K: No effect on methylation by PRMT1."
FT /evidence="ECO:0000269|PubMed:22095282"
FT MUTAGEN 78
FT /note="R->K: Reduced methylation by PRMT1. Abolishes
FT methylation by PRMT1 and PRMT1-mediated inhibition of
FT MAPK35 activation; when associated with K-80."
FT /evidence="ECO:0000269|PubMed:22095282"
FT MUTAGEN 80
FT /note="R->K: Reduced methylation by PRMT1. Abolishes
FT methylation by PRMT1 and PRMT1-mediated inhibition of
FT MAPK35 activation; when associated with K-78."
FT /evidence="ECO:0000269|PubMed:22095282"
FT MUTAGEN 709
FT /note="K->M: Loss of kinase activity. Inhibits activation
FT of JNK and apoptosis mediated by TNFRSF6 and DAXX. Does not
FT affect interaction with TRIM48."
FT /evidence="ECO:0000269|PubMed:17210579,
FT ECO:0000269|PubMed:29186683, ECO:0000269|PubMed:9743501"
FT MUTAGEN 709
FT /note="K->R: Loss of kinase activity. Abolishes DAXX-
FT mediated apoptosis. Loss of RC3H2-mediated ubiquitination."
FT /evidence="ECO:0000269|PubMed:17210579,
FT ECO:0000269|PubMed:24448648, ECO:0000269|PubMed:9743501"
FT MUTAGEN 838
FT /note="T->A: Does not affect interaction with TRIM48."
FT /evidence="ECO:0000269|PubMed:29186683"
FT MUTAGEN 966
FT /note="S->A: Enhanced induction of apoptosis, increased
FT kinase activity, and loss of YWHAG binding."
FT /evidence="ECO:0000269|PubMed:10411906,
FT ECO:0000269|PubMed:15094778"
FT MUTAGEN 1033
FT /note="S->A: Enhanced induction of apoptosis and increased
FT kinase activity."
FT /evidence="ECO:0000269|PubMed:15094778"
FT HELIX 273..286
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 289..303
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 311..323
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 327..339
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 345..347
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 349..362
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 367..379
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 387..403
FT /evidence="ECO:0007829|PDB:5ULM"
FT TURN 404..406
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 409..425
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 429..441
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 452..466
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 469..471
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 475..487
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 491..503
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 508..524
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 536..548
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 557..564
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 570..578
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 581..583
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 585..592
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 601..605
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 606..608
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 609..614
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 621..626
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 633..636
FT /evidence="ECO:0007829|PDB:5ULM"
FT HELIX 640..654
FT /evidence="ECO:0007829|PDB:5ULM"
FT STRAND 673..675
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 681..683
FT /evidence="ECO:0007829|PDB:2CLQ"
FT STRAND 685..688
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 690..699
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 700..702
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 705..712
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 716..718
FT /evidence="ECO:0007829|PDB:5UOX"
FT HELIX 719..729
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 740..746
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 749..755
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 758..761
FT /evidence="ECO:0007829|PDB:4BF2"
FT HELIX 762..768
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 774..776
FT /evidence="ECO:0007829|PDB:5V19"
FT HELIX 777..796
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 806..808
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 809..811
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 813..815
FT /evidence="ECO:0007829|PDB:6E2N"
FT STRAND 818..820
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 823..825
FT /evidence="ECO:0007829|PDB:2CLQ"
FT STRAND 827..829
FT /evidence="ECO:0007829|PDB:2CLQ"
FT STRAND 832..835
FT /evidence="ECO:0007829|PDB:5VIL"
FT HELIX 843..845
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 848..851
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 854..857
FT /evidence="ECO:0007829|PDB:4BF2"
FT HELIX 861..876
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 882..884
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 887..897
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 909..918
FT /evidence="ECO:0007829|PDB:6E2N"
FT TURN 923..925
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 929..933
FT /evidence="ECO:0007829|PDB:6E2N"
FT HELIX 936..938
FT /evidence="ECO:0007829|PDB:4BF2"
SQ SEQUENCE 1374 AA; 154537 MW; 265BDC65968AF985 CRC64;
MSTEADEGIT FSVPPFAPSG FCTIPEGGIC RRGGAAAVGE GEEHQLPPPP PGSFWNVESA
AAPGIGCPAA TSSSSATRGR GSSVGGGSRR TTVAYVINEA SQGQLVVAES EALQSLREAC
ETVGATLETL HFGKLDFGET TVLDRFYNAD IAVVEMSDAF RQPSLFYHLG VRESFSMANN
IILYCDTNSD SLQSLKEIIC QKNTMCTGNY TFVPYMITPH NKVYCCDSSF MKGLTELMQP
NFELLLGPIC LPLVDRFIQL LKVAQASSSQ YFRESILNDI RKARNLYTGK ELAAELARIR
QRVDNIEVLT ADIVINLLLS YRDIQDYDSI VKLVETLEKL PTFDLASHHH VKFHYAFALN
RRNLPGDRAK ALDIMIPMVQ SEGQVASDMY CLVGRIYKDM FLDSNFTDTE SRDHGASWFK
KAFESEPTLQ SGINYAVLLL AAGHQFESSF ELRKVGVKLS SLLGKKGNLE KLQSYWEVGF
FLGASVLAND HMRVIQASEK LFKLKTPAWY LKSIVETILI YKHFVKLTTE QPVAKQELVD
FWMDFLVEAT KTDVTVVRFP VLILEPTKIY QPSYLSINNE VEEKTISIWH VLPDDKKGIH
EWNFSASSVR GVSISKFEER CCFLYVLHNS DDFQIYFCTE LHCKKFFEMV NTITEEKGRS
TEEGDCESDL LEYDYEYDEN GDRVVLGKGT YGIVYAGRDL SNQVRIAIKE IPERDSRYSQ
PLHEEIALHK HLKHKNIVQY LGSFSENGFI KIFMEQVPGG SLSALLRSKW GPLKDNEQTI
GFYTKQILEG LKYLHDNQIV HRDIKGDNVL INTYSGVLKI SDFGTSKRLA GINPCTETFT
GTLQYMAPEI IDKGPRGYGK AADIWSLGCT IIEMATGKPP FYELGEPQAA MFKVGMFKVH
PEIPESMSAE AKAFILKCFE PDPDKRACAN DLLVDEFLKV SSKKKKTQPK LSALSAGSNE
YLRSISLPVP VLVEDTSSSS EYGSVSPDTE LKVDPFSFKT RAKSCGERDV KGIRTLFLGI
PDENFEDHSA PPSPEEKDSG FFMLRKDSER RATLHRILTE DQDKIVRNLM ESLAQGAEEP
KLKWEHITTL IASLREFVRS TDRKIIATTL SKLKLELDFD SHGISQVQVV LFGFQDAVNK
VLRNHNIKPH WMFALDSIIR KAVQTAITIL VPELRPHFSL ASESDTADQE DLDVEDDHEE
QPSNQTVRRP QAVIEDAVAT SGVSTLSSTV SHDSQSAHRS LNVQLGRMKI ETNRLLEELV
RKEKELQALL HRAIEEKDQE IKHLKLKSQP IEIPELPVFH LNSSGTNTED SELTDWLRVN
GADEDTISRF LAEDYTLLDV LYYVTRDDLK CLRLRGGMLC TLWKAIIDFR NKQT
