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Activation of PI3Kalpha by Physiological Effectors and by Oncogenic Mutations: Structural and Dynamic Effects

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Air date: Wednesday, October 5, 2011, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
Views: Total views: 354, (69 Live, 285 On-demand)
Category: WALS - Wednesday Afternoon Lectures
Runtime: 01:04:21
Description: The lipid kinase PI3Kalpha is composed of two subunits: a catalytic subunit p110 and a regulatory subunit p85. Under basal conditions p85 has an inhibitory effect on the kinase activity.

Physiological activation of PI3Ka is the result of the release of the p85 inhibition when the nSH2 binds the phosphorylated tyrosine of activated receptors or their substrates. Oncogenic mutations of PI3Ka activate the enzyme constitutively triggering downstream pathways that increase tumor aggressiveness and survival. Structural information suggests that some of these mutations also activate the enzyme by releasing p85 inhibition. Others may use different mechanisms. For example, His1047Arg, the most common oncogenic mutation, causes a conformational change that increases membrane association and greater accessibility to the substrate, an integral membrane component. Activation of the enzyme by these effects appear to be the result of a combination of conformational changes and changes in the dynamics of loop and domain-domain motions.

The NIH Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.

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Author: L. Mario Amzel, Ph.D., Johns Hopkins University School of Medicine
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CIT Live ID: 10503
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