title: Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites.
abstract: Protein kinase autophosphorylation of activation segment residues is a common regulatory mechanism in phosphorylation-dependent signalling cascades. However, the molecular mechanisms that guarantee specific and efficient phosphorylation of these sites have not been elucidated. Here, we report on three novel and diverse protein kinase structures that reveal an exchanged activation segment conformation. This dimeric arrangement results in an active kinase conformation in trans, with activation segment phosphorylation sites in close proximity to the active site of the interacting protomer. Analytical ultracentrifugation and chemical cross-linking confirmed the presence of dimers in solution. Consensus substrate sequences for each kinase showed that the identified activation segment autophosphorylation sites are non-consensus substrate sites. Based on the presented structural and functional data, a model for specific activation segment phosphorylation at non-consensus substrate sites is proposed that is likely to be common to other kinases from diverse subfamilies.
authors.affiliation: Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Oxford, UK.
authors.forename: Ashley C W
authors.initials: AC
authors.lastname: Pike
authors.forename: Peter
authors.initials: P
authors.lastname: Rellos
authors.forename: Frank H
authors.initials: FH
authors.lastname: Niesen
authors.forename: Andrew
authors.initials: A
authors.lastname: Turnbull
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.forename: Sirlester A
authors.initials: SA
authors.lastname: Parker
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D011494:Protein Kinases