Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites

• Ashley C W Pike ^[2] ; Peter Rellos ^[2] ; Frank H Niesen ^[2] ; Andrew Turnbull ^[2] ; Antony W Oliver ^[3] ; Sirlester A Parker ^[1] ; Benjamin E Turk ^[1] ; Laurence H Pearl ^[3] ; Stefan Knapp ^[2]
  1. [1] Yale University

     Yale University

     Town of New Haven, Estados Unidos

     
  2. [2] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  3. [3] Cancer Research UK, DNA Repair Enzymes Group, Section of Structural Biology, The Institute of Cancer Research, Chelsea, London, UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 27, Nº. 4, 2008, págs. 704-714
• Idioma: inglés
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• Resumen

  • 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.