The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling
- Chu, Nam
- Viennet, Thibault
- Cole, Philip
- Arthanari, Haribabu
- Salguero, Antonieta
- Bae, Hwan
- Boeszoermenyi, Andras
DOIAbstract
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 activatio...
Add to ORKG