2vki

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Revision as of 08:26, 14 May 2008

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Template:STRUCTURE 2vki

STRUCTURE OF THE PDK1 PH DOMAIN K465E MUTANT

Overview

PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

About this Structure

2VKI is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance., Bayascas JR, Wullschleger S, Sakamoto K, Garcia-Martinez JM, Clacher C, Komander D, van Aalten DM, Boini KM, Lang F, Lipina C, Logie L, Sutherland C, Chudek JA, van Diepen JA, Voshol PJ, Lucocq JM, Alessi DR, Mol Cell Biol. 2008 May;28(10):3258-72. Epub 2008 Mar 17. PMID:18347057 Page seeded by OCA on Wed May 14 11:26:18 2008