Abstract
Cyclin A2 is essential at two critical points in the somatic cell cycle: during S phase, when it activates CDK2, and during the G2 to M transition when it activates CDK1. Based on the crystal structure of Cyclin A2 in association with CDKs, we generated a panel of mutants to characterize the specific amino acids required for partner binding, CDK activation and subcellular localization. We find that CDK1, CDK2, p21, p27 and p107 have overlapping but distinct requirements for association with this protein. Our data highlight the crucial importance of the N-terminal α helix, in conjunction with the α3 helix within the cyclin box, in activating CDK. Several Cyclin A2 mutants selectively bind to either CDK1 or CDK2. We demonstrate that association of Cyclin A2 to proteins such as CDK2 that was previously suggested as crucial is not a prerequisite for its nuclear localization, and we propose that the whole protein structure is involved.
Highlights
Cyclin-dependent kinases (CDK), that govern progression through the cell cycle, are mainly controlled by transient interactions with cyclin regulatory subunits and by reversible phosphorylation reactions [1,2]
Previous structural studies highlighted the importance of the hydrophobic region (MRAIL motif) of the first a helix within the cyclin box for molecular contacts of Cyclin A2 with CDK2 [14,15]
Mutagenesis carried out on the human Cyclin A2 pointed to amino acid residues M210A, L214A, W217A, as crucial for its association with RXL-containing
Summary
Cyclin-dependent kinases (CDK), that govern progression through the cell cycle, are mainly controlled by transient interactions with cyclin regulatory subunits and by reversible phosphorylation reactions [1,2]. Cyclin A2 is essential for at least two critical points in the somatic cell cycle: during the S phase, when it activates CDK2, and during the G2 to M transition when it activates CDK1. Phosphorylation of components of the DNA replication machinery such as CDC6 by Cyclin A-CDK is believed to be important to ensure only one round of DNA replication per cell cycle. A recent study demonstrated the implication of Cyclin A2 in the activation of the M-phase promoting complex composed of Cyclin B and CDK1 and that regulates G2-M transition [4]. A recently published work using mice with conditional Cyclin A2 alleles, while pointing to the compensatory effect brought about by Cyclin E2 in Cyclin A2 deficiency, confirmed its absolute requirement in early embryonic development and in the establishment of the hematopoietic lineage [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
