The Crystal Structure of Human Cyclin B

Petri, Edward T.; Errico, Alessia; Escobedo, Lourdes; Hunt, Tim; Basavappa, Ravi

doi:10.4161/cc.6.11.4297

Cited by 59 publications

(52 citation statements)

References 27 publications

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“…2A, Bottom). These results are in agreement with a previous study predicting the importance of the N-terminal helix (amino acids 183-194) in reinforcing contacts between cyclins and Cdks, as well as stimulation of kinase activity (26). The other constructs, including the entire CBOX2 after the CLS (302-432), did not bind Cdk and had no detectable associated kinase activity.…”

Section: Resultssupporting

confidence: 82%

Discovery of a distinct domain in cyclin A sufficient for centrosomal localization independently of Cdk binding

Pascreau

Eckerdt

Churchill

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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.centrosomal localization signal | p27 KIP1 | cell cycle | hydrophobic patch

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Section: Resultssupporting

confidence: 82%

Discovery of a distinct domain in cyclin A sufficient for centrosomal localization independently of Cdk binding

Pascreau

Eckerdt

Churchill

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…As pointed out above, after our study was completed, two crystal structures of cyclin B appeared in the literature. [43][44] We will see that our homology modeled structure is quite similar to this crystal structure, particularly in regions that are implicated in peptide interactions. Hence we will use our own structural work to derive our conclusions but use the crystal structure to test some of the properties that we compute.…”

Section: Introductionmentioning

confidence: 93%

“…The recently solved crystal structure of cyclin B (chain B of RCSB entry 2JGZ, resolved at 2.9 Å) 43,44 will be used as the reference structure. The Modeller 45 program was used for modeling the 3D structure of cyclin B1 based on the cyclin A2 template structure 41 since it has the highest identity with cyclin A2 (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Substrate Specificity of Cyclins Determined by Electrostatics

Lee

Chua²,

Krishnan³

et al. 2007

Cell Cycle

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ACKnowLeDGementSBII and IMCB are A-STAR institutes funded by BMRC. We thank Michael Schaefer for providing us with unpublished parameters for version 3 of the analytical continuum solvent method. AbStrACtCyclin 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 and 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.

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“…Three-dimensional structures are available for many CDK monomers (CDKs 2, 4, 5, 8 and 9) as well as cyclin/CDK dimers (cyclins A, B, C, H, T and p25/Pho80 in complex with their CDKs), [36][37][38][39][40][41][42] which provided a molecular understanding of how cyclins activate CDKs. 24,43,44 Like all kinases, cyclin-dependent kinases have a two-lobed structure.…”

Section: Conventional Cyclin-cdk Interactionsmentioning

confidence: 99%