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Title: Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling
Authors: Alexander, Jes
Lim, Daniel
Joughin, Brian A.
Hegemann, Björn
Hutchins, James R. A.
Ehrenberger, Tobias
Ivins, Frank
Sessa, Fabio
Hudecz, Otto
Nigg, Erich A.
Fry, Andrew M.
Musacchio, Andrea
Stukenberg, P. Todd
Mechtler, Karl
Peters, Jan-Michael
Smerdon, Stephen J.
Yaffe, Michael B.
First Published: 28-Jun-2011
Publisher: American Association for the Advancement of Science
Citation: Science Signaling, 2011, 4 (179), ra42
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.
DOI Link: 10.1126/scisignal.2001796
ISSN: 1945-0877
eISSN: 1937-9145
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2011, The Authors. Deposited with reference to the publisher’s open access archiving policy.
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling, 2011, 4 (179), ra42, DOI: 10.1126/scisignal.2001796.
Appears in Collections:Published Articles, Dept. of Biochemistry

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