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Substrate Specificity of Cyclins Determined by Electrostatics

Hui Jun Lee, Gek Huey Chua, Arun Krishnan, David P. Lane and Chandra S. Verma

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Cyclin dependent kinases (CDK) associate with Cyclins to regulate cell cycle progression and gene transcription by phosphorylating key proteins. The different Cyclin-CDK complexes display differences in substrate specificities with substrates binding across a shallow, hydrophobic, substrate binding pocket known as the Cyclin groove. However the mechanism underlying this differential substrate recognition remains largely unknown and cannot be explained merely on the basis of sequence variability. A subset of Cyclins, Cyclins A2, E1 and B1 despite being structurally and functionally similar, show marked differences in their interactions with recruitment peptides derived from their substrate or inhibitor proteins p27, p21, p57, E2F1, p53, pRb, and p107. While these peptides (characterized by a Cyclin Binding motif of four residues ZRXL where Z and X are cationic residues) inhibit the activity of Cyclins A2 and E1, no such inhibition is observed for Cyclin B1. Electrostatic potentials of Cyclins A2, E1 and B1 show that anionic regions of Cyclins A2 and E1 enable them to bind peptides while cationic regions at homologous locations in Cyclin B1 abrogate binding. These arise from charged residues that are conserved. Mutations that switch these characters are suggested. Computed energetics of binding confirms this. Deregulation of the enzymatic activity of this class of enzymes is a ubiquitous feature of human neoplasia, but attempts to exploit this therapeutically have been confounded by a lack of understanding of the precise specificity of the different Cyclin complexes. Here we begin to clarify this issue by explaining the mechanism by which Cyclin B1 escapes regulation by the p21 family of CDKIs.

Authors

Hui Jun Lee

Bioinformatics Institute; Matrix, Singapore

Gek Huey Chua

Bioinformatics Institute; Matrix, Singapore

Arun Krishnan

Bioinformatics Institute; Matrix, Singapore

David P. Lane

Institute for Molecular and Cellular Biology; Proteos, Singapore

Chandra S. Verma

Bioinformatics Institute; Matrix, Singapore

Purchase article for $19

Subscribe to this journal for $129/year