title: Structural mechanism for the specific assembly and activation of the extracellular signal regulated kinase 5 (ERK5) module.
abstract: Mitogen-activated protein kinase (MAPK) activation depends on a linear binding motif found in all MAPK kinases (MKK). In addition, the PB1 (Phox and Bem1) domain of MKK5 is required for extracellular signal regulated kinase 5 (ERK5) activation. We present the crystal structure of ERK5 in complex with an MKK5 construct comprised of the PB1 domain and the linear binding motif. We show that ERK5 has distinct protein-protein interaction surfaces compared with ERK2, which is the closest ERK5 paralog. The two MAPKs have characteristically different physiological functions and their distinct protein-protein interaction surface topography enables them to bind different sets of activators and substrates. Structural and biochemical characterization revealed that the MKK5 PB1 domain cooperates with the MAPK binding linear motif to achieve substrate specific binding, and it also enables co-recruitment of the upstream activating enzyme and the downstream substrate into one signaling competent complex. Studies on present day MAPKs and MKKs hint on the way protein kinase networks may evolve. In particular, they suggest how paralogous enzymes with similar catalytic properties could acquire novel signaling roles by merely changing the way they make physical links to other proteins.
authors: Department of Biochemistry, Eötvös Loránd University, Budapest H-1117, Hungary.
authors: Gábor
authors: G
authors: Glatz
authors: Department of Biochemistry, Eötvös Loránd University, Budapest H-1117, Hungary.
authors: Gergő
authors: G
authors: Gógl
authors: Department of Biochemistry, Eötvös Loránd University, Budapest H-1117, Hungary.
authors: Anita
authors: A
authors: Alexa
authors: Department of Biochemistry, Eötvös Loránd University, Budapest H-1117, Hungary. Electronic address: remenyi@elte.hu.
authors: Attila
authors: A
authors: Reményi
mesh_terms: D000595:Amino Acid Sequence; D001051:Apoenzymes / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000737:chemistry; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry; D048054:Mitogen-Activated Protein Kinase 7 / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013499:Surface Properties
chemical_list: D001051:Apoenzymes; D046912:Multiprotein Complexes; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5
references: Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):486-9
references: 23519423
references: Biochem J. 2004 Aug 1;381(Pt 3):693-9
references: 15132737
references: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
references: 20057044
references: Nat Cell Biol. 2000 Feb;2(2):110-6
references: 10655591
references: Mol Cell. 2006 Sep 1;23(5):631-40
references: 16949360
references: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9697-702
references: 16766652
references: Nature. 1994 Feb 24;367(6465):704-11
references: 8107865
references: PLoS One. 2011;6(10):e26999
references: 22046431
references: EMBO J. 1997 Dec 1;16(23):7054-66
references: 9384584
references: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references: 19461840
references: Sci Signal. 2012 Oct 09;5(245):ra74
references: 23047924
references: J Biol Chem. 2005 Jan 28;280(4):2659-67
references: 15548525
references: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references: 21460441
references: Mol Cell. 2005 Dec 22;20(6):951-62
references: 16364919
references: Arch Biochem Biophys. 2006 May 15;449(1-2):8-16
references: 16626623
references: J Biol Chem. 2001 Mar 16;276(11):7927-31
references: 11118448
references: Nat Neurosci. 2001 Oct;4(10):981-8
references: 11544482
references: Trends Cell Biol. 2009 Aug;19(8):364-74
references: 19651513
references: Structure. 2010 Nov 10;18(11):1502-11
references: 21070949
references: Biochemistry. 2011 May 10;50(18):3660-72
references: 21449613
references: J Biol Chem. 2009 Jul 17;284(29):19392-401
references: 19473979
references: Mol Cell Biol. 2006 Mar;26(6):2065-79
references: 16507987
references: J Biol Chem. 2002 Nov 8;277(45):43344-51
references: 12221099
references: Annu Rev Biochem. 2006;75:655-80
references: 16756506
references: Biochim Biophys Acta. 2012 Jan;1825(1):37-48
references: 22020294
references: J Biol Chem. 2009 May 8;284(19):13165-73
references: 19196711
references: J Clin Invest. 2004 Apr;113(8):1138-48
references: 15085193
references: Science. 2006 Feb 10;311(5762):822-6
references: 16424299
references: Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9809-14
references: 21628578
references: Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5326-31
references: 16567630
references: Genes Dev. 1999 Jan 15;13(2):163-75
references: 9925641
references: Mol Cell. 2002 Jun;9(6):1241-9
references: 12086621
references: J Neurosci. 2001 Jan 15;21(2):434-43
references: 11160424
references: Science. 1995 Jan 20;267(5196):389-93
references: 7824938
references: BMC Bioinformatics. 2005 Dec 01;6 Suppl 4:S20
references: 16351747
references: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references: 20383002
references: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8532-7
references: 12826611
references: Nature. 2003 Dec 11;426(6967):676-80
references: 14668868
references: Biochim Biophys Acta. 2007 Aug;1773(8):1376-87
references: 17161475
references: Mol Cell Biol. 2006 Mar;26(5):1679-90
references: 16478989
references: Nature. 1998 Oct 15;395(6703):713-6
references: 9790194
references: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9248-53
references: 12093914
references: J Biol Chem. 2003 Sep 26;278(39):36989-92
references: 12912994
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references: 20124702
references: Biochemistry. 2007 Nov 27;46(47):13478-89
references: 17985933
references: Cell Signal. 2006 Jun;18(6):753-60
references: 16376520
references: J Mol Evol. 1999 Nov;49(5):567-82
references: 10552038
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references: 20124692
references: Development. 2007 Dec;134(23):4131-40
references: 17959722
references: Trends Biochem Sci. 2000 Sep;25(9):448-53
references: 10973059
references: Oncogene. 2007 May 14;26(22):3100-12
references: 17496909
references: Structure. 2006 Jun;14(6):1011-9
references: 16765894
references: Mol Cell Biol. 2007 Jun;27(12):4566-77
references: 17452462
references: J Biol Chem. 2008 Jun 6;283(23):15903-11
references: 18408005
references: EMBO Rep. 2006 Aug;7(8):782-6
references: 16880823
references: Mol Cell Biol. 2008 Apr;28(7):2481-94
references: 18212044
references: J Biol Chem. 1995 May 26;270(21):12665-9
references: 7759517
references: Sci Signal. 2011 Jun 28;4(179):ra42
references: 21712545