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Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling

Alexander, J. and Lim, D. and Joughin, B. A. and Hegemann, B. and Hutchins, J. R. A. and Ehrenberger, T. and Ivins, F. and Sessa, F. and Hudecz, O. and Nigg, E. A. and Fry, A. M. and Musacchio, A. and Stukenberg, P. T. and Mechtler, K. and Peters, J. -M. and Smerdon, S. J. and Yaffe, M. B.. (2011) Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling. Science Signaling, Vol. 4, H. 179 , ra42.

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Official URL: http://edoc.unibas.ch/dok/A5844170

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Abstract

The timing and localization of events during mitosis are controlled by the regulated phosphorylation of proteins by the mitotic kinases, which include Aurora A, Aurora B, Nek2 (never in mitosis kinase 2), Plk1 (Polo-like kinase 1), and the cyclin-dependent kinase complex Cdk1/cyclin B. Although mitotic kinases can have overlapping subcellular localizations, each kinase appears to phosphorylate its substrates on distinct sites. To gain insight into the relative importance of local sequence context in kinase selectivity, identify previously unknown substrates of these five mitotic kinases, and explore potential mechanisms for substrate discrimination, we determined the optimal substrate motifs of these major mitotic kinases by positional scanning oriented peptide library screening (PS-OPLS). We verified individual motifs with in vitro peptide kinetic studies and used structural modeling to rationalize the kinase-specific selection of key motif-determining residues at the molecular level. Cross comparisons among the phosphorylation site selectivity motifs of these kinases revealed an evolutionarily conserved mutual exclusion mechanism in which the positively and negatively selected portions of the phosphorylation motifs of mitotic kinases, together with their subcellular localizations, result in proper substrate targeting in a coordinated manner during mitosis.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Cell Biology (Nigg)
UniBasel Contributors:Nigg, Erich A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for the Advancement of Science
ISSN:1937-9145
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:17
Deposited On:14 Sep 2012 06:42

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