Structure of the phosphoinositide 3-kinase p110γ-p101 complex reveals molecular mechanism of GPCR activation
Manoj K. Rathinaswamy,Udit Dalwadi,Kaelin D. Fleming,Carson Adams,Jordan T B Stariha,Els Pardon,Minkyung Baek,Oscar Vadas,Frank DiMaio,Jan Steyaert,Scott D. Hansen,Calvin K. Yip,John E. Burke,John E. Burke +13 more
TLDR
In this paper, the authors reported the structure of a heterodimeric PI3K-gamma complex, p110{gamma}-p101, which reveals a unique assembly of catalytic and regulatory subunits.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.read more
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