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The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling

Citation

Chu, Nam et al. (2020), The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling, Dryad, Dataset, https://doi.org/10.5061/dryad.0p2ngf1xg

Abstract

Akt is a critical protein kinase that governs cancer cell growth and metabolism. Akt appears to be autoinhibited by an intramolecular interaction between its N-terminal pleckstrin homology (PH) domain and kinase domain, which is relieved by C-tail phosphorylation, but the precise molecular mechanisms remain elusive. Here we use a combination of protein semisynthesis, NMR, and enzymological analysis to characterize structural features of the PH domain in its autoinhibited and activated states. We find that Akt autoinhibition depends on the length/tension of the PH-kinase linker. We identify a role for a dynamic short segment in the PH domain that appears to regulate autoinhibition and PDK1-catalyzed phosphorylation of Thr308 in the activation loop. We determine that Akt allosteric inhibitor MK2206 drives distinct PH domain structural changes compared to baseline autoinhibited Akt. These results highlight how the conformational plasticity of Akt governs the delicate control of its catalytic properties.

Funding

National Institutes of Health, Award: CA74305

Claudia Adams Barr Program for Innovative Cancer Research

Austrian Science Fund, Award: Schrödinger Fellowship J3872-B21

Kwanjeong Educational Foundation

American Heart Association, Award: Fellowship 19POST34380800

National Institutes of Health, Award: EB002026

Claudia Adams Barr Program for Innovative Cancer Research