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Deota, S. and Rathnachalam, S. and Namrata, K. and Boob, M. and Fulzele, A. and Radhika, S. and Ganguli, S. and Balaji, C. and Kaypee, S. and Vishwakarma, K.K. and Kundu, T.K. and Bhandari, Rashna and de Peredo, A.G. and Mishra, M. and Venkatramani, R. and Kolthur-Seetharam, U. (2019) Allosteric Regulation of Cyclin-B Binding by the Charge State of Catalytic Lysine in CDK1 Is Essential for Cell Cycle Progression. Journal of Molecular Biology, 431 (11). pp. 2127-2142. ISSN 0022-2836

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Cyclin dependent kinase 1 (CDK1) is essential for cell cycle progression. While dependence of CDK activity on cyclin levels is well established, molecular mechanisms that regulate their binding are less understood. Here, we report for the first time that CDK1:cyclin-B binding is not default but rather determined by the evolutionarily conserved catalytic residue, lysine-33 in CDK1. We demonstrate that the charge state of this lysine allosterically remodels the CDK1:cyclin-B interface. Cell cycle dependent acetylation of lysine-33 or its mutation to glutamine, which mimics acetylation, abrogates cyclin-B binding. Using both biochemical approaches and atomistic molecular dynamics simulations, we have uncovered both short-range and long-range effects of perturbing the charged state of the catalytic lysine, which leads to inhibition of kinase activity. Specifically, although loss of the charge state of catalytic lysine did not impact ATP binding significantly, it altered its orientation in the active site. In addition, the catalytic lysine also acts as an intra-molecular electrostatic tether at the active site to orient structural elements interfacing with cyclin-B. Physiologically, opposing activities of SIRT1 and P300 regulate acetylation and thus control the charge state of lysine-33. Importantly, cells expressing acetylation mimic mutant of Cdc2/CDK1 in yeast are arrested in G2 and fail to divide, indicating the requirement of the deacetylated state of the catalytic lysine for cell division. Thus, by illustrating the molecular role of the catalytic lysine and cell cycle dependent deacetylation as a determinant of CDK1:cyclin-B interaction, our results redefine the current model of CDK1 activation and cell cycle progression

Item Type: Article
Uncontrolled Keywords: Deacetylation G2-M progression Kinase activity PSTAIRE-helix SIRT1
Subjects: Cell Biology
Depositing User: Dr P Divakar
Date Deposited: 13 Apr 2019 19:55
Last Modified: 30 May 2019 10:50
URI: http://cdfd.sciencecentral.in/id/eprint/892

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