Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 7, Pages 2932-2937Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914874107
Keywords
centrosomal localization signal; p27(KIP1); cell cycle; hydrophobic patch
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Funding
- Howard Hughes Medical Institute and National Institutes of Health [GM79154]
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Centrosomes have recently emerged as key regulators of the cell cycle. The G1/S transition requires a functional centrosome, and centrosomal localization of numerous proteins, including cyclin/Cdk complexes, is important for the G2/M transition. Here we identify a modular centrosomal localization signal (CLS) localizing cyclin A to centrosomes independently of Cdk binding. The cyclin A CLS is located in a distinct part of the molecule compared with the cyclin E CLS and includes the MRAIL hydrophobic patch involved in substrate recognition. The cyclin A CLS interacts with p27(KIP1), and expression of p27(KIP1) removes cyclin A but not cyclin E from centrosomes. Expression of the cyclin A CLS displaces both endogenous cyclin A and E from centrosomes and inhibits DNA replication, supporting an emerging concept that DNA replication is linked to centrosomal events. Structural analysis indicates that differences in surface charge and length of the C-terminal helix explain why the MRAIL region in cyclin E is not a functional CLS. These results indicate that the cyclin A CLS may contribute to targeting and recognition of centrosomal Cdk substrates and is required for specific effects of p27(KIP1) on cyclin A-Cdk2.
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