ID M4K2_HUMAN Reviewed; 820 AA. AC Q12851; Q86VU3; DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 24-JAN-2024, entry version 208. DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 2; DE EC=2.7.11.1; DE AltName: Full=B lymphocyte serine/threonine-protein kinase; DE AltName: Full=Germinal center kinase; DE Short=GC kinase; DE AltName: Full=MAPK/ERK kinase kinase kinase 2; DE Short=MEK kinase kinase 2; DE Short=MEKKK 2; DE AltName: Full=Rab8-interacting protein; GN Name=MAP4K2; Synonyms=GCK, RAB8IP; 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 {ECO:0000312|EMBL:AAA20968.1}; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Uterus; 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 [4] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-820 (ISOFORM 1), FUNCTION, DOMAIN, AND RP TISSUE SPECIFICITY. RC TISSUE=Tonsil; RX PubMed=7515885; DOI=10.1016/s0021-9258(19)89463-2; RA Katz P., Whalen G., Kehrl J.H.; RT "Differential expression of a novel protein kinase in human B lymphocytes. RT Preferential localization in the germinal center."; RL J. Biol. Chem. 269:16802-16809(1994). RN [5] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=7477268; DOI=10.1038/377750a0; RA Pombo C.M., Kehrl J.H., Sanchez I., Katz P., Avruch J., Zon L.I., RA Woodgett J.R., Force T., Kyriakis J.M.; RT "Activation of the SAPK pathway by the human STE20 homologue germinal RT centre kinase."; RL Nature 377:750-754(1995). RN [6] RP FUNCTION, AUTOPHOSPHORYLATION, AND INTERACTION WITH MAP3K1/MEKK1 AND TRAF2. RX PubMed=9712898; DOI=10.1074/jbc.273.35.22681; RA Yuasa T., Ohno S., Kehrl J.H., Kyriakis J.M.; RT "Tumor necrosis factor signaling to stress-activated protein kinase RT (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase RT couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and RT SAPK while receptor interacting protein associates with a mitogen-activated RT protein kinase kinase kinase upstream of MKK6 and p38."; RL J. Biol. Chem. 273:22681-22692(1998). RN [7] {ECO:0000305} RP FUNCTION, AND INTERACTION WITH TRAF2 AND MAP3K1. RX PubMed=11784851; DOI=10.1128/mcb.22.3.737-749.2002; RA Chadee D.N., Yuasa T., Kyriakis J.M.; RT "Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 RT by the Ste20p homologue GCK and the adapter protein TRAF2."; RL Mol. Cell. Biol. 22:737-749(2002). RN [8] RP ACTIVITY REGULATION, FUNCTION, UBIQUITINATION, AND INTERACTION WITH TRAF6. RX PubMed=15456887; DOI=10.1128/mcb.24.20.9165-9175.2004; RA Zhong J., Kyriakis J.M.; RT "Germinal center kinase is required for optimal Jun N-terminal kinase RT activation by Toll-like receptor agonists and is regulated by the ubiquitin RT proteasome system and agonist-induced, TRAF6-dependent stabilization."; RL Mol. Cell. Biol. 24:9165-9175(2004). RN [9] RP FUNCTION, AND INTERACTION WITH MAP3K11/MLK3. RX PubMed=17584736; DOI=10.1074/jbc.m703422200; RA Zhong J., Kyriakis J.M.; RT "Dissection of a signaling pathway by which pathogen-associated molecular RT patterns recruit the JNK and p38 MAPKs and trigger cytokine release."; RL J. Biol. Chem. 282:24246-24254(2007). RN [10] RP REVIEW ON FUNCTION. RX PubMed=10026130; DOI=10.1074/jbc.274.9.5259; RA Kyriakis J.M.; RT "Signaling by the germinal center kinase family of protein kinases."; RL J. Biol. Chem. 274:5259-5262(1999). RN [11] RP REVIEW ON FUNCTION. RX PubMed=11316611; DOI=10.1016/s0962-8924(01)01980-8; RA Dan I., Watanabe N.M., Kusumi A.; RT "The Ste20 group kinases as regulators of MAP kinase cascades."; RL Trends Cell Biol. 11:220-230(2001). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND IDENTIFICATION BY RP 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 [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, 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 [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-328 AND SER-394, AND RP IDENTIFICATION BY 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 [16] 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). CC -!- FUNCTION: Serine/threonine-protein kinase which acts as an essential CC component of the MAP kinase signal transduction pathway. Acts as a MAPK CC kinase kinase kinase (MAP4K) and is an upstream activator of the CC stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) CC signaling pathway and to a lesser extent of the p38 MAPKs signaling CC pathway. Required for the efficient activation of JNKs by TRAF6- CC dependent stimuli, including pathogen-associated molecular patterns CC (PAMPs) such as polyinosine-polycytidine (poly(IC)), CC lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial CC flagellin. To a lesser degree, IL-1 and engagement of CD40 also CC stimulate MAP4K2-mediated JNKs activation. The requirement for CC MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS CC stimulation of c-Jun phosphorylation and induction of IL-8. Enhances CC MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 CC autoinhibition and lead to activation following autophosphorylation. CC Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling CC pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. CC May play a role in the regulation of vesicle targeting or fusion. CC regulation of vesicle targeting or fusion. CC {ECO:0000269|PubMed:11784851, ECO:0000269|PubMed:15456887, CC ECO:0000269|PubMed:17584736, ECO:0000269|PubMed:7477268, CC ECO:0000269|PubMed:7515885, ECO:0000269|PubMed:9712898}. 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:7515885}; 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:7515885}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:7515885}; CC -!- ACTIVITY REGULATION: The tumor necrosis factor (TNF), as well as CC endotoxins and pro-inflammatory stimuli such as polyinosine- CC polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan CC (PGN), flagellin, or lipid A activate MAP4K2 by promoting its CC autophosphorylation. {ECO:0000269|PubMed:15456887, CC ECO:0000269|PubMed:7477268}. CC -!- SUBUNIT: Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. CC Interacts with RAB8A (By similarity). {ECO:0000250}. CC -!- INTERACTION: CC Q12851; Q13233: MAP3K1; NbExp=2; IntAct=EBI-49783, EBI-49776; CC Q12851; Q9NUX5: POT1; NbExp=2; IntAct=EBI-49783, EBI-752420; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Basolateral cell CC membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. CC Golgi apparatus membrane {ECO:0000250}; Peripheral membrane protein CC {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q12851-1; Sequence=Displayed; CC Name=2; CC IsoId=Q12851-2; Sequence=VSP_054134; CC -!- TISSUE SPECIFICITY: Highly expressed in germinal center but not mantle CC zone B-cells. Also expressed in lung, brain and placenta and at lower CC levels in other tissues examined. {ECO:0000269|PubMed:7515885}. CC -!- DOMAIN: The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. CC Proteins with PEST domains are frequently targets of degradation by the CC ubiquitin proteasome. {ECO:0000269|PubMed:7515885}. CC -!- PTM: Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing CC proteasomal turnover. Ubiquitination requires the kinase activity of CC MAP4K2/GCK. {ECO:0000269|PubMed:15456887}. CC -!- PTM: Autophosphorylated in response to tumor necrosis factor (TNF), CC endotoxins or pro-inflammatory stimuli. Autophosphorylation leads to CC activation. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr CC protein kinase family. STE20 subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA20968.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AP001462; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471076; EAW74302.1; -; Genomic_DNA. DR EMBL; BC047865; AAH47865.1; -; mRNA. DR EMBL; U07349; AAA20968.1; ALT_SEQ; mRNA. DR CCDS; CCDS8082.1; -. [Q12851-1] DR CCDS; CCDS81582.1; -. [Q12851-2] DR PIR; A53714; A53714. DR RefSeq; NP_001294919.1; NM_001307990.1. [Q12851-2] DR RefSeq; NP_004570.2; NM_004579.4. [Q12851-1] DR AlphaFoldDB; Q12851; -. DR SMR; Q12851; -. DR BioGRID; 111809; 99. DR IntAct; Q12851; 17. DR MINT; Q12851; -. DR STRING; 9606.ENSP00000294066; -. DR BindingDB; Q12851; -. DR ChEMBL; CHEMBL5330; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q12851; -. DR GuidetoPHARMACOLOGY; 2086; -. DR iPTMnet; Q12851; -. DR PhosphoSitePlus; Q12851; -. DR BioMuta; MAP4K2; -. DR DMDM; 215274019; -. DR CPTAC; CPTAC-2864; -. DR CPTAC; CPTAC-2865; -. DR CPTAC; CPTAC-862; -. DR CPTAC; CPTAC-863; -. DR EPD; Q12851; -. DR jPOST; Q12851; -. DR MassIVE; Q12851; -. DR MaxQB; Q12851; -. DR PaxDb; 9606-ENSP00000294066; -. DR PeptideAtlas; Q12851; -. DR ProteomicsDB; 58984; -. [Q12851-1] DR ProteomicsDB; 70069; -. DR Pumba; Q12851; -. DR Antibodypedia; 2060; 284 antibodies from 28 providers. DR DNASU; 5871; -. DR Ensembl; ENST00000294066.7; ENSP00000294066.2; ENSG00000168067.12. [Q12851-1] DR Ensembl; ENST00000377350.7; ENSP00000366567.3; ENSG00000168067.12. [Q12851-2] DR GeneID; 5871; -. DR KEGG; hsa:5871; -. DR MANE-Select; ENST00000294066.7; ENSP00000294066.2; NM_004579.5; NP_004570.2. DR UCSC; uc001obh.4; human. [Q12851-1] DR AGR; HGNC:6864; -. DR CTD; 5871; -. DR DisGeNET; 5871; -. DR GeneCards; MAP4K2; -. DR HGNC; HGNC:6864; MAP4K2. DR HPA; ENSG00000168067; Low tissue specificity. DR MIM; 603166; gene. DR neXtProt; NX_Q12851; -. DR OpenTargets; ENSG00000168067; -. DR PharmGKB; PA30610; -. DR VEuPathDB; HostDB:ENSG00000168067; -. DR eggNOG; KOG0576; Eukaryota. DR GeneTree; ENSGT00940000162250; -. DR InParanoid; Q12851; -. DR OMA; DTANNPE; -. DR OrthoDB; 152877at2759; -. DR PhylomeDB; Q12851; -. DR TreeFam; TF105121; -. DR PathwayCommons; Q12851; -. DR SignaLink; Q12851; -. DR SIGNOR; Q12851; -. DR BioGRID-ORCS; 5871; 37 hits in 1162 CRISPR screens. DR GeneWiki; MAP4K2; -. DR GenomeRNAi; 5871; -. DR Pharos; Q12851; Tchem. DR PRO; PR:Q12851; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q12851; Protein. DR Bgee; ENSG00000168067; Expressed in granulocyte and 118 other cell types or tissues. DR ExpressionAtlas; Q12851; baseline and differential. DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0000139; C:Golgi membrane; TAS:ProtInc. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0008349; F:MAP kinase kinase kinase kinase activity; IBA:GO_Central. DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IPI: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:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0007254; P:JNK cascade; TAS:ProtInc. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB. DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0006903; P:vesicle targeting; IEA:Ensembl. DR CDD; cd06613; STKc_MAP4K3_like; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR001180; CNH_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR021160; MAPKKKK. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR PANTHER; PTHR48012:SF6; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 2; 1. DR PANTHER; PTHR48012; STERILE20-LIKE KINASE, ISOFORM B-RELATED; 1. DR Pfam; PF00780; CNH; 1. DR Pfam; PF00069; Pkinase; 1. DR PIRSF; PIRSF038172; MAPKKKK; 1. DR SMART; SM00036; CNH; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50219; CNH; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q12851; HS. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Cell membrane; Cytoplasm; KW Golgi apparatus; Immunity; Innate immunity; Kinase; Membrane; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Stress response; Transferase; KW Ubl conjugation. FT CHAIN 1..820 FT /note="Mitogen-activated protein kinase kinase kinase FT kinase 2" FT /id="PRO_0000086275" FT DOMAIN 16..273 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 482..793 FT /note="CNH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00795" FT REGION 294..314 FT /note="PEST1" FT REGION 344..360 FT /note="PEST2" FT REGION 387..442 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 405..448 FT /note="PEST3" FT COMPBIAS 409..438 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 136 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 22..30 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 45 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 394 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 426..433 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_054134" FT CONFLICT 120 FT /note="A -> R (in Ref. 4; AAA20968)" FT /evidence="ECO:0000305" SQ SEQUENCE 820 AA; 91556 MW; A59C1E99BFFAEF41 CRC64; MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD PGDDISSLQQ EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE IYHATGPLEE RQIAYVCREA LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV KLADFGVSGE LTASVAKRRS FIGTPYWMAP EVAAVERKGG YNELCDVWAL GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT RWTQNFHHFL KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG TIKRAPFLGP LPTDPPAEEP LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ REDPERSSCH GLPPTPKVHM GACFSKVFNG CPLRIHAAVT WIHPVTRDQF LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL LSLSGKSTHI WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM LEPLVLDGKE LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI PGSAQQVIQV DRDTILVSFE RCVRIVNMQG EPTATLAPEL TFDFPIETVV CLQDSVLAFW SHGMQGRSLD TNEVTQEITD ETRIFRVLGA HRDIILESIP TDNPEAHSNL YILTGHQSTY //