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The Ys and wherefores of protein kinase autoinhibition

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journal contribution
posted on 20.05.2015, 09:43 by Richard Bayliss, Tamanna Haq, Sharon Yeoh
Protein phosphorylation is a key reaction in the regulation of cellular events and is catalysed by over 500 protein kinases in humans. The activities of protein kinases are strictly controlled through a diverse set of mechanisms. Structural studies have shown that the conformation adopted by kinases in their active state is highly similar, whereas inactive kinases can adopt a variety of conformations. Many kinases are maintained in a catalytically inactive state through autoinhibition. This involves a conformation of the kinase active site that is unable to support catalysis and requires activation through a signal such as binding of a regulatory protein. In this review, we briefly summarise some of the well-established autoinhibitory mechanisms and then focus on a relatively unexplored mode of autoinhibition that was first discovered in the Nek family of kinases and is also relevant to IRE1. This involves a tyrosine side-chain that blocks the active site and which must undergo a conformational change to enable kinase activity. We have termed this the Tyr-down autoinhibitory mechanism. We summarise the evidence for this mechanism and describe its role in kinase inhibitor design. Finally, we survey the kinome to identify other kinases with the potential to be governed by an autoinhibitory Tyr-down mechanism. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Funding

Research in the Bayliss group relating to this review is funded by grants from Cancer Research UK (C24461/A12772 and C24461/A13231) and the Medical Research Council (MR/L017032/1).

History

Citation

Biochim Biophys Acta, 2015

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry

Version

AM (Accepted Manuscript)

Published in

Biochim Biophys Acta

Publisher

Elsevier

issn

0006-3002

Copyright date

2015

Available date

30/04/2016

Publisher version

http://www.sciencedirect.com/science/article/pii/S157096391500134X

Language

en

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