title: A cancer-derived mutation in the PSTAIRE helix of cyclin-dependent kinase 2 alters the stability of cyclin binding.
abstract: 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.
authors.affiliation: Department of Life Sciences, Imperial College, South Kensington, London SW72AZ, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Child
authors.forename: Tereza
authors.initials: T
authors.lastname: Hendrychová
authors.forename: Karen
authors.initials: K
authors.lastname: McCague
authors.forename: Andy
authors.initials: A
authors.lastname: Futreal
authors.forename: Michal
authors.initials: M
authors.lastname: Otyepka
authors.forename: David J
authors.initials: DJ
authors.lastname: Mann
mesh_terms: 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
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
references.citation: Cell Cycle. 2006 Jun;5(12):1313-9
references.pmid: 16775416
references.citation: EMBO J. 1999 Feb 1;18(3):654-63
references.pmid: 9927425
references.citation: Oncogene. 2002 Nov 21;21(53):8067-74
references.pmid: 12444543
references.citation: Nat Struct Biol. 1996 Aug;3(8):696-700
references.pmid: 8756328
references.citation: Mol Cell. 1999 Sep;4(3):353-63
references.pmid: 10518216
references.citation: Anal Biochem. 2005 Oct 15;345(2):187-97
references.pmid: 16140252
references.citation: Curr Opin Cell Biol. 1994 Apr;6(2):239-46
references.pmid: 7517688
references.citation: Mol Cell Biol. 2003 Oct;23(20):7285-90
references.pmid: 14517297
references.citation: J Biol Chem. 2006 Mar 17;281(11):7271-81
references.pmid: 16407256
references.citation: J Comput Chem. 2003 Dec;24(16):1999-2012
references.pmid: 14531054
references.citation: J Med Chem. 2006 Nov 2;49(22):6500-9
references.pmid: 17064068
references.citation: Nat Rev Cancer. 2009 Mar;9(3):153-66
references.pmid: 19238148
references.citation: Nature. 1995 Jul 27;376(6538):313-20
references.pmid: 7630397
references.citation: Cell Cycle. 2008 Apr 1;7(7):892-8
references.pmid: 18414028
references.citation: Nat Rev Cancer. 2001 Dec;1(3):222-31
references.pmid: 11902577
references.citation: Protein Sci. 2004 Jun;13(6):1449-57
references.pmid: 15133164
references.citation: Protein Sci. 2005 Feb;14(2):445-51
references.pmid: 15632290
references.citation: Genetics. 1996 Dec;144(4):1425-36
references.pmid: 8978031
references.citation: Nature. 2009 Apr 9;458(7239):719-24
references.pmid: 19360079
references.citation: Science. 2005 Feb 4;307(5710):690-6
references.pmid: 15692043
references.citation: EMBO J. 2005 Feb 9;24(3):452-63
references.pmid: 15660127
references.citation: J Mol Model. 2008 Aug;14(8):761-8
references.pmid: 18470542