A cancer-derived mutation in the PSTAIRE helix of cyclin-dependent kinase 2 alters the stability of cyclin binding.
Cyclin-dependent kinase 2 (cdk2) is a central regulator of the mammalian cell cycle. Here we describe the properties of a mutant form of cdk2 identified during large-scale sequencing of protein kinases from cancerous tissue. The mutation substituted a leucine for a proline in the PSTAIRE helix, the central motif in the interaction of the cdk with its regulatory cyclin subunit. We demonstrate that whilst the mutant cdk2 is considerably impaired in stable cyclin association, it is still able to generate an active kinase that can functionally complement defective cdks in vivo. Molecular dynamic simulations and biophysical measurements indicate that the observed biochemical properties likely stem from increased flexibility within the cyclin-binding helix.
Child
Emma S
ES
Department of Life Sciences, Imperial College, South Kensington, London SW72AZ, UK.
Hendrychová
Tereza
T
McCague
Karen
K
Futreal
Andy
A
Otyepka
Michal
M
Mann
David J
DJ
D000818:Animals; D002460:Cell Line; D002942:Circular Dichroism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
Cell Cycle. 2006 Jun;5(12):1313-9
16775416
EMBO J. 1999 Feb 1;18(3):654-63
9927425
Oncogene. 2002 Nov 21;21(53):8067-74
12444543
Nat Struct Biol. 1996 Aug;3(8):696-700
8756328
Mol Cell. 1999 Sep;4(3):353-63
10518216
Anal Biochem. 2005 Oct 15;345(2):187-97
16140252
Curr Opin Cell Biol. 1994 Apr;6(2):239-46
7517688
Mol Cell Biol. 2003 Oct;23(20):7285-90
14517297
J Biol Chem. 2006 Mar 17;281(11):7271-81
16407256
J Comput Chem. 2003 Dec;24(16):1999-2012
14531054
J Med Chem. 2006 Nov 2;49(22):6500-9
17064068
Nat Rev Cancer. 2009 Mar;9(3):153-66
19238148
Nature. 1995 Jul 27;376(6538):313-20
7630397
Cell Cycle. 2008 Apr 1;7(7):892-8
18414028
Nat Rev Cancer. 2001 Dec;1(3):222-31
11902577
Protein Sci. 2004 Jun;13(6):1449-57
15133164
Protein Sci. 2005 Feb;14(2):445-51
15632290
Genetics. 1996 Dec;144(4):1425-36
8978031
Nature. 2009 Apr 9;458(7239):719-24
19360079
Science. 2005 Feb 4;307(5710):690-6
15692043
EMBO J. 2005 Feb 9;24(3):452-63
15660127
J Mol Model. 2008 Aug;14(8):761-8
18470542