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Title: The Ys and wherefores of protein kinase autoinhibition
Authors: Bayliss, Richard
Haq, Tamanna
Yeoh, Sharon
First Published: 30-Apr-2015
Publisher: Elsevier
Citation: Biochim Biophys Acta, 2015
Abstract: 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.
DOI Link: 10.1016/j.bbapap.2015.04.025
ISSN: 0006-3002
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Archived with reference to SHERPA/RoMEO and publisher website. © 2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Appears in Collections:Published Articles, Dept. of Biochemistry

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