Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation

Proceedings of the National Academy of Sciences of the United States of America
Julia A CallenderAlexandra C Newton

Abstract

Conventional protein kinase C (PKC) family members are reversibly activated by binding to the second messengers Ca2+ and diacylglycerol, events that break autoinhibitory constraints to allow the enzyme to adopt an active, but degradation-sensitive, conformation. Perturbing these autoinhibitory constraints, resulting in protein destabilization, is one of many mechanisms by which PKC function is lost in cancer. Here, we address how a gain-of-function germline mutation in PKCα in Alzheimer's disease (AD) enhances signaling without increasing vulnerability to down-regulation. Biochemical analyses of purified protein demonstrate that this mutation results in an ∼30% increase in the catalytic rate of the activated enzyme, with no changes in the concentrations of Ca2+ or lipid required for half-maximal activation. Molecular dynamics simulations reveal that this mutation has both localized and allosteric effects, most notably decreasing the dynamics of the C-helix, a key determinant in the catalytic turnover of kinases. Consistent with this mutation not altering autoinhibitory constraints, live-cell imaging studies reveal that the basal signaling output of PKCα-M489V is unchanged. However, the mutant enzyme in cells displays increased ...Continue Reading

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Citations

Jul 18, 2018·Nature Neuroscience·Mark L Dell'Acqua, Kevin M Woolfrey
Feb 25, 2020·Current Alzheimer Research·Marta KowalskaJolanta Dorszewska
Feb 6, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Dahlia TriningsihYoun Ju Lee
Oct 6, 2020·Advances in Biological Regulation·Nilufar RahimovaMarcelo G Kazanietz
Apr 17, 2021·Trends in Endocrinology and Metabolism : TEM·Devanshi Mishra, Chinmoy Sankar Dey

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