DAPK3_HUMAN
ID DAPK3_HUMAN Reviewed; 454 AA.
AC O43293; A0AVN4; B3KQE2; Q05JY4;
DT 28-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Death-associated protein kinase 3;
DE Short=DAP kinase 3;
DE EC=2.7.11.1 {ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979, ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:18995835};
DE AltName: Full=DAP-like kinase;
DE Short=Dlk;
DE AltName: Full=MYPT1 kinase;
DE AltName: Full=Zipper-interacting protein kinase;
DE Short=ZIP-kinase;
GN Name=DAPK3; Synonyms=ZIPK;
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] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9488481; DOI=10.1128/mcb.18.3.1642;
RA Kawai T., Matsumoto M., Takeda K., Sanjo H., Akira S.;
RT "ZIP kinase, a novel serine/threonine kinase which mediates apoptosis.";
RL Mol. Cell. Biol. 18:1642-1651(1998).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR.
RC TISSUE=Cervix carcinoma;
RX PubMed=10356987; DOI=10.1016/s0014-5793(99)00550-5;
RA Murata-Hori M., Suizu F., Iwasaki T., Kikuchi A., Hosoya H.;
RT "ZIP kinase identified as a novel myosin regulatory light chain kinase in
RT HeLa cells.";
RL FEBS Lett. 451:81-84(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 MRNA].
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 165-454 (ISOFORM 2), ALTERNATIVE SPLICING,
RP FUNCTION IN PHOSPHORYLATION OF MYOSIN; PPP1R12A AND MYL12B, CATALYTIC
RP ACTIVITY, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION
RP WITH PPP1R12A AND MYOSIN, AUTOPHOSPHORYLATION, AND TISSUE SPECIFICITY.
RC TISSUE=Urinary bladder;
RX PubMed=17126281; DOI=10.1016/j.abb.2006.09.026;
RA Takamoto N., Komatsu S., Komaba S., Niiro N., Ikebe M.;
RT "Novel ZIP kinase isoform lacks leucine zipper.";
RL Arch. Biochem. Biophys. 456:194-203(2006).
RN [6]
RP FUNCTION IN PHOSPHORYLATION OF MUSCLE MYL12B, AND CATALYTIC ACTIVITY.
RX PubMed=11384979; DOI=10.1074/jbc.m102753200;
RA Niiro N., Ikebe M.;
RT "Zipper-interacting protein kinase induces Ca(2+)-free smooth muscle
RT contraction via myosin light chain phosphorylation.";
RL J. Biol. Chem. 276:29567-29574(2001).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF NON-MUSCLE MYL12B, AND CATALYTIC ACTIVITY.
RX PubMed=11781833; DOI=10.1038/sj.onc.1205055;
RA Murata-Hori M., Fukuta Y., Ueda K., Iwasaki T., Hosoya H.;
RT "HeLa ZIP kinase induces diphosphorylation of myosin II regulatory light
RT chain and reorganization of actin filaments in nonmuscle cells.";
RL Oncogene 20:8175-8183(2001).
RN [8] {ECO:0000305}
RP FUNCTION IN APOPTOSIS, AND INTERACTION WITH DAXX AND PAWR.
RX PubMed=12917339; DOI=10.1128/mcb.23.17.6174-6186.2003;
RA Kawai T., Akira S., Reed J.C.;
RT "ZIP kinase triggers apoptosis from nuclear PML oncogenic domains.";
RL Mol. Cell. Biol. 23:6174-6186(2003).
RN [9]
RP INTERACTION WITH PPP1R12A, AND TISSUE SPECIFICITY.
RX PubMed=15292222; DOI=10.1074/jbc.m403676200;
RA Endo A., Surks H.K., Mochizuki S., Mochizuki N., Mendelsohn M.E.;
RT "Identification and characterization of zipper-interacting protein kinase
RT as the unique vascular smooth muscle myosin phosphatase-associated
RT kinase.";
RL J. Biol. Chem. 279:42055-42061(2004).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF MYL12B, AND CATALYTIC ACTIVITY.
RX PubMed=15096528; DOI=10.1083/jcb.200309056;
RA Komatsu S., Ikebe M.;
RT "ZIP kinase is responsible for the phosphorylation of myosin II and
RT necessary for cell motility in mammalian fibroblasts.";
RL J. Cell Biol. 165:243-254(2004).
RN [11]
RP FUNCTION, PHOSPHORYLATION AT THR-299; SER-309; SER-311; SER-312; SER-318
RP AND SER-326, PHOSPHORYLATION BY DAPK1, AND SUBCELLULAR LOCATION.
RX PubMed=15367680; DOI=10.1128/mcb.24.19.8611-8626.2004;
RA Shani G., Marash L., Gozuacik D., Bialik S., Teitelbaum L., Shohat G.,
RA Kimchi A.;
RT "Death-associated protein kinase phosphorylates ZIP kinase, forming a
RT unique kinase hierarchy to activate its cell death functions.";
RL Mol. Cell. Biol. 24:8611-8626(2004).
RN [12]
RP INTERACTION WITH STAT3.
RX PubMed=16219639; DOI=10.1093/intimm/dxh331;
RA Sato N., Kawai T., Sugiyama K., Muromoto R., Imoto S., Sekine Y.,
RA Ishida M., Akira S., Matsuda T.;
RT "Physical and functional interactions between STAT3 and ZIP kinase.";
RL Int. Immunol. 17:1543-1552(2005).
RN [13]
RP INTERACTION WITH TCP10L, AND SUBCELLULAR LOCATION.
RX PubMed=15910542; DOI=10.1111/j.1365-2605.2005.00522.x;
RA Yu H., Jiang D., Guo Z., Saiyin H., Guo J., Wang X., Yu L.;
RT "TCP10L is expressed specifically in spermatogenic cells and binds to death
RT associated protein kinase-3.";
RL Int. J. Androl. 28:163-170(2005).
RN [14]
RP PHOSPHORYLATION AT THR-180; THR-225; THR-265; THR-299; THR-306 AND SER-311,
RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF THR-299;
RP 299-THR-THR-300; VAL-427; VAL-434 AND LEU-441.
RX PubMed=15611134; DOI=10.1074/jbc.m412538200;
RA Graves P.R., Winkfield K.M., Haystead T.A.;
RT "Regulation of zipper-interacting protein kinase activity in vitro and in
RT vivo by multisite phosphorylation.";
RL J. Biol. Chem. 280:9363-9374(2005).
RN [15]
RP REVIEW ON FUNCTION.
RX PubMed=16756490; DOI=10.1146/annurev.biochem.75.103004.142615;
RA Bialik S., Kimchi A.;
RT "The death-associated protein kinases: structure, function, and beyond.";
RL Annu. Rev. Biochem. 75:189-210(2006).
RN [16]
RP FUNCTION, ACTIVITY REGULATION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT
RP THR-180; THR-265 AND THR-299, AND MUTAGENESIS OF LYS-42; ASP-161; THR-225;
RP THR-265 AND THR-299.
RX PubMed=17158456; DOI=10.1074/jbc.m609990200;
RA Hagerty L., Weitzel D.H., Chambers J., Fortner C.N., Brush M.H.,
RA Loiselle D., Hosoya H., Haystead T.A.;
RT "ROCK1 phosphorylates and activates zipper-interacting protein kinase.";
RL J. Biol. Chem. 282:4884-4893(2007).
RN [17]
RP SUBCELLULAR LOCATION, AND ABSENCE OF INTERACTION WITH PARW.
RX PubMed=17953487; DOI=10.1371/journal.pgen.0030180;
RA Shoval Y., Pietrokovski S., Kimchi A.;
RT "ZIPK: a unique case of murine-specific divergence of a conserved
RT vertebrate gene.";
RL PLoS Genet. 3:1884-1893(2007).
RN [18]
RP REVIEW ON FUNCTION.
RX DOI=10.1002/sita.200600112;
RA Scheidtmann K.H.;
RT "Dlk/ZIP kinase, a novel Ser/Thr-specific protein kinase with multiple
RT functions.";
RL Signal Transduct. 7:248-259(2007).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF RPL13A, AND CATALYTIC ACTIVITY.
RX PubMed=18995835; DOI=10.1016/j.molcel.2008.09.019;
RA Mukhopadhyay R., Ray P.S., Arif A., Brady A.K., Kinter M., Fox P.L.;
RT "DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating
RT inflammatory gene expression.";
RL Mol. Cell 32:371-382(2008).
RN [20]
RP FUNCTION IN ANDROGEN RECEPTOR-MEDIATED TRANSCRIPTION.
RX PubMed=18084323; DOI=10.1038/sj.onc.1210995;
RA Leister P., Felten A., Chasan A.I., Scheidtmann K.H.;
RT "ZIP kinase plays a crucial role in androgen receptor-mediated
RT transcription.";
RL Oncogene 27:3292-3300(2008).
RN [21]
RP FUNCTION AS TUMOR SUPPRESSOR, CHARACTERIZATION OF VARIANTS MET-112; ASN-161
RP AND SER-216, MUTAGENESIS OF THR-180, AND SELF-ASSOCIATION.
RX PubMed=21487036; DOI=10.1158/0008-5472.can-10-3543;
RA Brognard J., Zhang Y.W., Puto L.A., Hunter T.;
RT "Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-
RT suppressing kinase.";
RL Cancer Res. 71:3152-3161(2011).
RN [22]
RP PHOSPHORYLATION AT THR-299, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 294-ARG-ARG-295.
RX PubMed=20854903; DOI=10.1016/j.cellsig.2010.09.016;
RA Weitzel D.H., Chambers J., Haystead T.A.;
RT "Phosphorylation-dependent control of ZIPK nuclear import is species
RT specific.";
RL Cell. Signal. 23:297-303(2011).
RN [23]
RP FUNCTION IN REGULATION OF AUTOPHAGY, AND INTERACTION WITH ULK1.
RX PubMed=21169990; DOI=10.1038/emboj.2010.338;
RA Tang H.W., Wang Y.B., Wang S.L., Wu M.H., Lin S.Y., Chen G.C.;
RT "Atg1-mediated myosin II activation regulates autophagosome formation
RT during starvation-induced autophagy.";
RL EMBO J. 30:636-651(2011).
RN [24]
RP FUNCTION, AND INTERACTION WITH NLK.
RX PubMed=21454679; DOI=10.1074/jbc.m110.189829;
RA Togi S., Ikeda O., Kamitani S., Nakasuji M., Sekine Y., Muromoto R.,
RA Nanbo A., Oritani K., Kawai T., Akira S., Matsuda T.;
RT "Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-
RT catenin signaling through interaction with Nemo-like kinase and T-cell
RT factor 4 (NLK/TCF4).";
RL J. Biol. Chem. 286:19170-19177(2011).
RN [25]
RP FUNCTION, AND INTERACTION WITH ATF4.
RX PubMed=21408167; DOI=10.1371/journal.pone.0017344;
RA Shoval Y., Berissi H., Kimchi A., Pietrokovski S.;
RT "New modularity of DAP-kinases: alternative splicing of the DRP-1 gene
RT produces a ZIPk-like isoform.";
RL PLoS ONE 6:E17344-E17344(2011).
RN [26]
RP FUNCTION IN REORGANIZATION OF ACTIN CYTOSKELETON, AND INTERACTION WITH
RP RHOD.
RX PubMed=23454120; DOI=10.1016/j.bbrc.2013.02.046;
RA Nehru V., Almeida F.N., Aspenstrom P.;
RT "Interaction of RhoD and ZIP kinase modulates actin filament assembly and
RT focal adhesion dynamics.";
RL Biochem. Biophys. Res. Commun. 433:163-169(2013).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-312, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [28]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 1-277.
RA Kursula P., Vahokoski J., Wilmanns M.;
RT "Crystal structure of human ZIP kinase.";
RL Submitted (JUN-2006) to the PDB data bank.
RN [29] {ECO:0007744|PDB:2J90}
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 9-289 IN COMPLEX WITH PYRIDONE-6,
RP ACTIVITY REGULATION, SUBUNIT, AND PHOSPHORYLATION AT SER-50 AND THR-265.
RX PubMed=18239682; DOI=10.1038/emboj.2008.8;
RA Pike A.C., Rellos P., Niesen F.H., Turnbull A., Oliver A.W., Parker S.A.,
RA Turk B.E., Pearl L.H., Knapp S.;
RT "Activation segment dimerization: a mechanism for kinase
RT autophosphorylation of non-consensus sites.";
RL EMBO J. 27:704-714(2008).
RN [30]
RP VARIANTS [LARGE SCALE ANALYSIS] MET-112; ASN-161 AND SER-216.
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 is involved in the regulation
CC of apoptosis, autophagy, transcription, translation and actin
CC cytoskeleton reorganization. Involved in the regulation of smooth
CC muscle contraction. Regulates both type I (caspase-dependent) apoptotic
CC and type II (caspase-independent) autophagic cell deaths signal,
CC depending on the cellular setting. Involved in regulation of
CC starvation-induced autophagy. Regulates myosin phosphorylation in both
CC smooth muscle and non-muscle cells. In smooth muscle, regulates myosin
CC either directly by phosphorylating MYL12B and MYL9 or through
CC inhibition of smooth muscle myosin phosphatase (SMPP1M) via
CC phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to
CC enhance muscle responsiveness to Ca(2+) and promote a contractile
CC state. Phosphorylates MYL12B in non-muscle cells leading to
CC reorganization of actin cytoskeleton. Isoform 2 can phosphorylate
CC myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of
CC actin stress fibers into thick bundles. Involved in actin filament
CC focal adhesion dynamics. The function in both reorganization of actin
CC cytoskeleton and focal adhesion dissolution is modulated by RhoD.
CC Positively regulates canonical Wnt/beta-catenin signaling through
CC interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon
CC interferon-gamma activation which is causing RPL13A release from the
CC ribosome, RPL13A association with the GAIT complex and its subsequent
CC involvement in transcript-selective translation inhibition. Enhances
CC transcription from AR-responsive promoters in a hormone- and kinase-
CC dependent manner. Involved in regulation of cell cycle progression and
CC cell proliferation. May be a tumor suppressor.
CC {ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979,
CC ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:12917339,
CC ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:15367680,
CC ECO:0000269|PubMed:16219639, ECO:0000269|PubMed:17126281,
CC ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18084323,
CC ECO:0000269|PubMed:18995835, ECO:0000269|PubMed:21169990,
CC ECO:0000269|PubMed:21408167, ECO:0000269|PubMed:21454679,
CC ECO:0000269|PubMed:21487036, ECO:0000269|PubMed:23454120}.
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=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979,
CC ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:15096528,
CC ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:18995835};
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=2.7.11.1; Evidence={ECO:0000269|PubMed:10356987,
CC ECO:0000269|PubMed:11384979, ECO:0000269|PubMed:11781833,
CC ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:17126281,
CC ECO:0000269|PubMed:18995835};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10356987};
CC -!- ACTIVITY REGULATION: A sequential activation is proposed:
CC autophosphorylation at consensus sites is leading to dimerization of
CC the catalytic domain stabilized by phosphorylation at Ser-50 and
CC activation segment exchange (producing an active confirmation of both
CC kinase modules in trans) followed by phosphorylation at Thr-180 in the
CC activation segment and at other regulatory sites (Probable).
CC Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for
CC activity. Oligomerization is required for full enzymatic activity.
CC Inhibited by pyridone-6 (K00225), a potent, ATP-competitive inhibitor.
CC {ECO:0000269|PubMed:15611134, ECO:0000269|PubMed:17158456,
CC ECO:0000269|PubMed:18239682, ECO:0000303|PubMed:18239682}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=12 uM for myosin (isoform 2) {ECO:0000269|PubMed:17126281};
CC KM=6.2 uM for myosin (isoform 1) {ECO:0000269|PubMed:17126281};
CC KM=73 uM for MYL12B (isoform 2) {ECO:0000269|PubMed:17126281};
CC KM=10.4 uM for MYL12B (isoform 1) {ECO:0000269|PubMed:17126281};
CC Vmax=248 nmol/min/mg enzyme toward myosin (isoform 2)
CC {ECO:0000269|PubMed:17126281};
CC Vmax=120 nmol/min/mg enzyme toward myosin (isoform 1)
CC {ECO:0000269|PubMed:17126281};
CC Vmax=1.3 umol/min/mg enzyme toward MYL12B (isoform 2)
CC {ECO:0000269|PubMed:17126281};
CC Vmax=271 nmol/min/mg enzyme toward MYL12B (isoform 1)
CC {ECO:0000269|PubMed:17126281};
CC -!- SUBUNIT: Homooligomer in its kinase-active form (homotrimers and
CC homodimers are reported); monomeric in its kinase-inactive form.
CC Homodimerization is required for activation segment autophosphorylation
CC (Probable). Isoform 1 and isoform 2 interact with myosin and PPP1R12A;
CC interaction of isoform 1 with PPP1R12A is inhibited by RhoA dominant
CC negative form. Interacts with NLK, DAXX, STAT3, RHOD (GTP-bound form)
CC and TCP10L. Interacts with PAWR; the interaction is reported
CC conflictingly: according to PubMed:17953487 does not interact with
CC PAWR. Interacts with ULK1; may be a substrate of ULK1.
CC {ECO:0000269|PubMed:12917339, ECO:0000269|PubMed:15292222,
CC ECO:0000269|PubMed:15910542, ECO:0000269|PubMed:16219639,
CC ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:18239682,
CC ECO:0000269|PubMed:21169990, ECO:0000269|PubMed:21408167,
CC ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:23454120,
CC ECO:0000303|PubMed:18239682}.
CC -!- INTERACTION:
CC O43293; O43293: DAPK3; NbExp=3; IntAct=EBI-77293, EBI-77293;
CC O43293; Q9UBE8: NLK; NbExp=3; IntAct=EBI-77293, EBI-366978;
CC O43293; O14974: PPP1R12A; NbExp=5; IntAct=EBI-77293, EBI-351726;
CC O43293; Q8TDR4: TCP10L; NbExp=5; IntAct=EBI-77293, EBI-3923210;
CC O43293-2; Q10728: Ppp1r12a; Xeno; NbExp=2; IntAct=EBI-9691390, EBI-918263;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15367680,
CC ECO:0000269|PubMed:15910542, ECO:0000269|PubMed:20854903}. Cytoplasm
CC {ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:15611134,
CC ECO:0000269|PubMed:17953487, ECO:0000269|PubMed:20854903}.
CC Note=Predominantly localizes to the cytoplasm but can shuttle between
CC the nucleus and cytoplasm; cytoplasmic localization is promoted by
CC phosphorylation at Thr-299 and involves Rho/Rock signaling.
CC {ECO:0000269|PubMed:17953487, ECO:0000269|PubMed:20854903}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Nucleus
CC {ECO:0000269|PubMed:17126281}. Cytoplasm {ECO:0000269|PubMed:17126281}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:17126281}. Cytoplasm {ECO:0000269|PubMed:17126281}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=ZIPK-L;
CC IsoId=O43293-1; Sequence=Displayed;
CC Name=2; Synonyms=ZIPK-S;
CC IsoId=O43293-2; Sequence=VSP_042059, VSP_042060;
CC -!- TISSUE SPECIFICITY: Widely expressed. Isoform 1 and isoform 2 are
CC expressed in the bladder smooth muscle. {ECO:0000269|PubMed:15292222,
CC ECO:0000269|PubMed:17126281}.
CC -!- PTM: The phosphorylation status is critical for kinase activity,
CC oligomerization and intracellular localization. Phosphorylation at Thr-
CC 180, Thr-225 and Thr-265 is essential for activity. The phosphorylated
CC form is localized in the cytoplasm promoted by phosphorylation at Thr-
CC 299; nuclear translocation or retention is maximal when it is not
CC phosphorylated. Phosphorylation increases the trimeric form, and its
CC dephosphorylation favors a kinase-inactive monomeric form. Both isoform
CC 1 and isoform 2 can undergo autophosphorylation.
CC {ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:15611134,
CC ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:20854903}.
CC -!- MISCELLANEOUS: [Isoform 2]: The internal splice site between exon 8 and
CC the 3' UTR, which yields this truncated isoform, is non-canonical.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. DAP kinase subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; AB007144; BAA24955.1; -; mRNA.
DR EMBL; AB022341; BAA81746.1; -; mRNA.
DR EMBL; AK074799; BAG52004.1; -; mRNA.
DR EMBL; BC126430; AAI26431.1; -; mRNA.
DR EMBL; BC126432; AAI26433.1; -; mRNA.
DR EMBL; AB265224; BAF34614.1; -; mRNA.
DR CCDS; CCDS12116.1; -. [O43293-1]
DR RefSeq; NP_001339.1; NM_001348.2. [O43293-1]
DR RefSeq; XP_005259565.1; XM_005259508.1.
DR PDB; 1YRP; X-ray; 3.10 A; A/B=1-277.
DR PDB; 2J90; X-ray; 2.00 A; A/B=9-289.
DR PDB; 3BHY; X-ray; 1.24 A; A=9-289.
DR PDB; 3BQR; X-ray; 1.75 A; A=9-289.
DR PDB; 5A6N; X-ray; 1.70 A; A/B=9-289.
DR PDB; 5A6O; X-ray; 1.60 A; A/B=9-289.
DR PDB; 5VJA; X-ray; 2.46 A; A/B/C/D=9-289.
DR PDBsum; 1YRP; -.
DR PDBsum; 2J90; -.
DR PDBsum; 3BHY; -.
DR PDBsum; 3BQR; -.
DR PDBsum; 5A6N; -.
DR PDBsum; 5A6O; -.
DR PDBsum; 5VJA; -.
DR AlphaFoldDB; O43293; -.
DR SMR; O43293; -.
DR BioGRID; 107983; 79.
DR IntAct; O43293; 61.
DR MINT; O43293; -.
DR STRING; 9606.ENSP00000442973; -.
DR BindingDB; O43293; -.
DR ChEMBL; CHEMBL2468; -.
DR DrugBank; DB07242; (4R)-7,8-dichloro-1',9-dimethyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrile.
DR DrugBank; DB04716; 2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-one.
DR DrugBank; DB07125; 4-(6-{[(1R)-1-(hydroxymethyl)propyl]amino}imidazo[1,2-b]pyridazin-3-yl)benzoic acid.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; O43293; -.
DR GuidetoPHARMACOLOGY; 2004; -.
DR iPTMnet; O43293; -.
DR PhosphoSitePlus; O43293; -.
DR BioMuta; DAPK3; -.
DR EPD; O43293; -.
DR jPOST; O43293; -.
DR MassIVE; O43293; -.
DR MaxQB; O43293; -.
DR PaxDb; O43293; -.
DR PeptideAtlas; O43293; -.
DR PRIDE; O43293; -.
DR ProteomicsDB; 48863; -. [O43293-1]
DR ProteomicsDB; 48864; -. [O43293-2]
DR Antibodypedia; 11137; 421 antibodies from 43 providers.
DR DNASU; 1613; -.
DR Ensembl; ENST00000301264.7; ENSP00000301264.3; ENSG00000167657.14. [O43293-1]
DR Ensembl; ENST00000545797.7; ENSP00000442973.1; ENSG00000167657.14. [O43293-1]
DR GeneID; 1613; -.
DR KEGG; hsa:1613; -.
DR MANE-Select; ENST00000545797.7; ENSP00000442973.1; NM_001348.3; NP_001339.1.
DR UCSC; uc002lzc.2; human. [O43293-1]
DR CTD; 1613; -.
DR DisGeNET; 1613; -.
DR GeneCards; DAPK3; -.
DR HGNC; HGNC:2676; DAPK3.
DR HPA; ENSG00000167657; Low tissue specificity.
DR MIM; 603289; gene.
DR neXtProt; NX_O43293; -.
DR OpenTargets; ENSG00000167657; -.
DR PharmGKB; PA27144; -.
DR VEuPathDB; HostDB:ENSG00000167657; -.
DR eggNOG; KOG0032; Eukaryota.
DR GeneTree; ENSGT00940000161753; -.
DR HOGENOM; CLU_000288_63_55_1; -.
DR InParanoid; O43293; -.
DR OMA; CRQKSNG; -.
DR PhylomeDB; O43293; -.
DR TreeFam; TF314166; -.
DR PathwayCommons; O43293; -.
DR Reactome; R-HSA-418889; Caspase activation via Dependence Receptors in the absence of ligand.
DR SABIO-RK; O43293; -.
DR SignaLink; O43293; -.
DR SIGNOR; O43293; -.
DR BioGRID-ORCS; 1613; 20 hits in 1112 CRISPR screens.
DR ChiTaRS; DAPK3; human.
DR EvolutionaryTrace; O43293; -.
DR GeneWiki; DAPK3; -.
DR GenomeRNAi; 1613; -.
DR Pharos; O43293; Tchem.
DR PRO; PR:O43293; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O43293; protein.
DR Bgee; ENSG00000167657; Expressed in apex of heart and 186 other tissues.
DR ExpressionAtlas; O43293; baseline and differential.
DR Genevisible; O43293; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0008140; F:cAMP response element binding protein binding; TAS:ParkinsonsUK-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0043522; F:leucine zipper domain binding; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IDA:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; IDA:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; TAS:UniProtKB.
DR GO; GO:2000145; P:regulation of cell motility; TAS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; IEA:Ensembl.
DR GO; GO:0051893; P:regulation of focal adhesion assembly; IDA:UniProtKB.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0007088; P:regulation of mitotic nuclear division; TAS:UniProtKB.
DR GO; GO:0043519; P:regulation of myosin II filament organization; IEA:Ensembl.
DR GO; GO:0006940; P:regulation of smooth muscle contraction; TAS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; TAS:UniProtKB.
DR CDD; cd14105; STKc_DAPK; 1.
DR InterPro; IPR042870; DAPK3_STKc.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 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; Activator; Alternative splicing; Apoptosis; ATP-binding;
KW Chromatin regulator; Cytoplasm; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transcription; Transcription regulation; Transferase;
KW Translation regulation; Tumor suppressor.
FT CHAIN 1..454
FT /note="Death-associated protein kinase 3"
FT /id="PRO_0000085914"
FT DOMAIN 13..275
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 161..204
FT /note="Activation segment"
FT /evidence="ECO:0000250|UniProtKB:O96017"
FT REGION 427..441
FT /note="Leucine-zipper"
FT /evidence="ECO:0000303|PubMed:9488481"
FT ACT_SITE 139
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 19..27
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 42
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 94
FT /ligand="pyridone 6"
FT /ligand_id="ChEBI:CHEBI:87103"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:18239682,
FT ECO:0007744|PDB:2J90"
FT BINDING 96
FT /ligand="pyridone 6"
FT /ligand_id="ChEBI:CHEBI:87103"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:18239682,
FT ECO:0007744|PDB:2J90"
FT MOD_RES 50
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18239682"
FT MOD_RES 180
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:15611134,
FT ECO:0000269|PubMed:17158456"
FT MOD_RES 225
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:15611134"
FT MOD_RES 265
FT /note="Phosphothreonine; by autocatalysis and ROCK1"
FT /evidence="ECO:0000269|PubMed:15611134,
FT ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18239682"
FT MOD_RES 299
FT /note="Phosphothreonine; by autocatalysis, DAPK1 and ROCK1"
FT /evidence="ECO:0000269|PubMed:15367680,
FT ECO:0000269|PubMed:15611134, ECO:0000269|PubMed:17158456,
FT ECO:0000269|PubMed:20854903"
FT MOD_RES 306
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:15611134"
FT MOD_RES 309
FT /note="Phosphoserine; by DAPK1"
FT /evidence="ECO:0000269|PubMed:15367680"
FT MOD_RES 311
FT /note="Phosphoserine; by autocatalysis and DAPK1"
FT /evidence="ECO:0000269|PubMed:15367680,
FT ECO:0000269|PubMed:15611134"
FT MOD_RES 312
FT /note="Phosphoserine; by DAPK1"
FT /evidence="ECO:0000269|PubMed:15367680,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 318
FT /note="Phosphoserine; by DAPK1"
FT /evidence="ECO:0000269|PubMed:15367680"
FT MOD_RES 326
FT /note="Phosphoserine; by DAPK1"
FT /evidence="ECO:0000269|PubMed:15367680"
FT VAR_SEQ 313..322
FT /note="LPPNNSYADF -> ASPIVAPVDA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17126281"
FT /id="VSP_042059"
FT VAR_SEQ 323..454
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17126281"
FT /id="VSP_042060"
FT VARIANT 112
FT /note="T -> M (in a colorectal adenocarcinoma sample;
FT somatic mutation; greatly reduces kinase activity,
FT increases cell proliferation and cell survival)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:21487036"
FT /id="VAR_040438"
FT VARIANT 161
FT /note="D -> N (in an ovarian mucinous carcinoma sample;
FT somatic mutation; greatly reduces kinase activity,
FT increases cell proliferation and cell survival)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:21487036"
FT /id="VAR_040439"
FT VARIANT 216
FT /note="P -> S (in a lung neuroendocrine carcinoma sample;
FT somatic mutation; greatly reduces kinase activity,
FT increases cell proliferation, cell adhesion and cell
FT survival)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:21487036"
FT /id="VAR_040440"
FT MUTAGEN 42
FT /note="K->A: Loss of kinase activity at low concentrations
FT of ATP."
FT /evidence="ECO:0000269|PubMed:17158456"
FT MUTAGEN 161
FT /note="D->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:17158456"
FT MUTAGEN 180
FT /note="T->A: Greatly reduced kinase activity."
FT /evidence="ECO:0000269|PubMed:21487036"
FT MUTAGEN 225
FT /note="T->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:17158456"
FT MUTAGEN 265
FT /note="T->A: Loss of phosphorylation by ROCK1,
FT catalytically inactive."
FT /evidence="ECO:0000269|PubMed:17158456"
FT MUTAGEN 294..295
FT /note="RR->AA: Cytoplasmic localization."
FT /evidence="ECO:0000269|PubMed:20854903"
FT MUTAGEN 299..300
FT /note="TT->AA: Predominantly nuclear localization."
FT /evidence="ECO:0000269|PubMed:15611134"
FT MUTAGEN 299
FT /note="T->A: Loss of phosphorylation by ROCK1."
FT /evidence="ECO:0000269|PubMed:17158456"
FT MUTAGEN 299
FT /note="T->D: Predominantly cytoplasmic localization;
FT phosphomimetic."
FT /evidence="ECO:0000269|PubMed:15611134"
FT MUTAGEN 427
FT /note="V->A: Predominantly nuclear localization; when
FT associated with A-434 and A-441."
FT /evidence="ECO:0000269|PubMed:15611134"
FT MUTAGEN 434
FT /note="V->A: Predominantly nuclear localization; when
FT associated with A-427 and A-441."
FT /evidence="ECO:0000269|PubMed:15611134"
FT MUTAGEN 441
FT /note="L->A: Predominantly nuclear localization; when
FT associated with A-427 and A-434."
FT /evidence="ECO:0000269|PubMed:15611134"
FT HELIX 9..12
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 13..21
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 23..32
FT /evidence="ECO:0007829|PDB:3BHY"
FT TURN 33..35
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 38..46
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 49..51
FT /evidence="ECO:0007829|PDB:2J90"
FT STRAND 53..56
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 58..70
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 79..84
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 86..94
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 101..108
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 113..132
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 142..144
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 145..148
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 150..154
FT /evidence="ECO:0007829|PDB:3BHY"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 171..175
FT /evidence="ECO:0007829|PDB:5A6N"
FT HELIX 176..178
FT /evidence="ECO:0007829|PDB:5A6O"
FT HELIX 181..183
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 186..189
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 197..212
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 222..230
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 238..241
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 246..253
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 260..262
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 266..271
FT /evidence="ECO:0007829|PDB:3BHY"
FT HELIX 273..280
FT /evidence="ECO:0007829|PDB:3BHY"
SQ SEQUENCE 454 AA; 52536 MW; 56773008A6A61CF0 CRC64;
MSTFRQEDVE DHYEMGEELG SGQFAIVRKC RQKGTGKEYA AKFIKKRRLS SSRRGVSREE
IEREVNILRE IRHPNIITLH DIFENKTDVV LILELVSGGE LFDFLAEKES LTEDEATQFL
KQILDGVHYL HSKRIAHFDL KPENIMLLDK NVPNPRIKLI DFGIAHKIEA GNEFKNIFGT
PEFVAPEIVN YEPLGLEADM WSIGVITYIL LSGASPFLGE TKQETLTNIS AVNYDFDEEY
FSNTSELAKD FIRRLLVKDP KRRMTIAQSL EHSWIKAIRR RNVRGEDSGR KPERRRLKTT
RLKEYTIKSH SSLPPNNSYA DFERFSKVLE EAAAAEEGLR ELQRSRRLCH EDVEALAAIY
EEKEAWYREE SDSLGQDLRR LRQELLKTEA LKRQAQEEAK GALLGTSGLK RRFSRLENRY
EALAKQVASE MRFVQDLVRA LEQEKLQGVE CGLR
