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Journal of molecular biology, 2020-11, Vol.432 (22), p.5849-5859
2020

Details

Autor(en) / Beteiligte
Titel
Structural Features that Distinguish Inactive and Active PI3K Lipid Kinases
Ist Teil von
  • Journal of molecular biology, 2020-11, Vol.432 (22), p.5849-5859
Ort / Verlag
England: Elsevier Ltd
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Elsevier ScienceDirect Journals Complete
Beschreibungen/Notizen
  • PI3K lipid kinases signal through the PI3K/Akt pathway, regulating cell growth and proliferation. While the structural features that distinguish between the active and inactive states of protein kinases are well established, that has not been the case for lipid kinases, and neither was the structural mechanism controlling the switch between the two states. Class I PI3Ks are obligate heterodimers with catalytic and regulatory subunits. Here, we analyze PI3K crystal structures. Structures with the nSH2 (inactive state) are featured by collapsed activation loop (a-loop) and an IN kinase domain helix 11 (kα11). In the active state, the a-loop is extended and kα11 in the OUT conformation. Our analysis suggests that the nSH2 domain in the regulatory subunit regulates activation, catalysis and autoinhibition through the a-loop. Inhibition, activation and catalytic scenarios are shared by class IA PI3Ks; the activation is mimicked by oncogenic mutations and the inhibition offers an allosteric inhibitor strategy. [Display omitted] •Comparison of the PI3K crystal structures uncovers the key structural features that distinguish the inactive and active PI3K conformations.•nSH2 domain in the p85 regulatory subunit affects the activation loop and the regulatory arch in kinase domain, controlling the switch between the inactive and active state of PI3Ks.•The identified activation mechanism of PI3K is mimicked by oncogenic mutations.

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