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 ORCID: https://orcid.org/0000-0002-4880-9963 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 European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH301 Biology
ISSN:	00928674
Last Modified:	22 Jun 2023 10:01
URI:	https://orca.cardiff.ac.uk/id/eprint/1087

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