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bioRxiv · 10.1101/2021.06.01.446612

Structure of the phosphoinositide 3-kinase p110γ-p101 complex reveals molecular mechanism of GPCR activation

Rathinaswamy, M. K.·Dalwadi, U.·Fleming, K. D.·Adams, C.·Stariha, J. T.·Pardon, E.·Baek, M.·Vadas, O.·DiMaio, F.·Steyaert, J.·Hansen, S. D.·Yip, C. K.·Burke, J. E.
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Abstract

The class IB phosphoinositide 3-kinase (PI3K), PI3K{gamma}, is a master regulator of immune cell function, and a promising drug target for both cancer and inflammatory diseases. Critical to PI3K{gamma} function is the association of the p110{gamma} catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G-protein coupled receptors (GPCRs). Here, we report the cryo-EM structure of a heterodimeric PI3K{gamma} complex, p110{gamma}-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its G{beta}{gamma} binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary G{beta}{gamma} binding site in p110{gamma}. Multiple oncogenic mutations mapped to these novel interfaces and enhanced G{beta}{gamma} activation. A nanobody that specifically binds to the p101-G{beta}{gamma} interface blocks activation providing a novel tool to study and target p110{gamma}-p101-specific signaling events in vivo.

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Rathinaswamy, M. K., Dalwadi, U., Fleming, K. D., Adams, C., Stariha, J. T., Pardon, E., Baek, M., Vadas, O., DiMaio, F., Steyaert, J., Hansen, S. D., Yip, C. K., Burke, J. E.. 2021-06-01. Structure of the phosphoinositide 3-kinase p110γ-p101 complex reveals molecular mechanism of GPCR activation. https://doi.org/10.1101/2021.06.01.446612

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