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Crystal structure of glycogen synthase kinase 3β : structural basis for phosphate-primed substrate specificity and autoinhibition

Dajani, Rana, Fraser, Elizabeth, Roe, S. Mark, Young, Neville, Good, Valerie, Dale, Trevor Clive and Pearl, Laurence H. 2001. Crystal structure of glycogen synthase kinase 3β : structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105 (6) , pp. 721-732. 10.1016/S0092-8674(01)00374-9

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Abstract

Glycogen synthase kinase 3β (GSK3β) plays a key role in insulin and Wnt signaling, phosphorylating downstream targets by default, and becoming inhibited following the extracellular signaling event. The crystal structure of human GSK3β shows a catalytically active conformation in the absence of activation-segment phosphorylation, with the sulphonate of a buffer molecule bridging the activation-segment and N-terminal domain in the same way as the phosphate group of the activation-segment phospho-Ser/Thr in other kinases. The location of this oxyanion binding site in the substrate binding cleft indicates direct coupling of P+4 phosphate-primed substrate binding and catalytic activation, explains the ability of GSK3β to processively hyperphosphorylate substrates with Ser/Thr pentad-repeats, and suggests a mechanism for autoinhibition in which the phosphorylated N terminus binds as a competitive pseudosubstrate with phospho-Ser 9 occupying the P+4 site.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
ISSN: 00928674
Last Modified: 04 Jun 2017 01:38
URI: http://orca.cf.ac.uk/id/eprint/1087

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