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Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which me...

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Autores principales: Rathinaswamy, Manoj K., Dalwadi, Udit, Fleming, Kaelin D., Adams, Carson, Stariha, Jordan T. B., Pardon, Els, Baek, Minkyung, Vadas, Oscar, DiMaio, Frank, Steyaert, Jan, Hansen, Scott D., Yip, Calvin K., Burke, John E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397274/
https://www.ncbi.nlm.nih.gov/pubmed/34452907
http://dx.doi.org/10.1126/sciadv.abj4282
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author Rathinaswamy, Manoj K.
Dalwadi, Udit
Fleming, Kaelin D.
Adams, Carson
Stariha, Jordan T. B.
Pardon, Els
Baek, Minkyung
Vadas, Oscar
DiMaio, Frank
Steyaert, Jan
Hansen, Scott D.
Yip, Calvin K.
Burke, John E.
author_facet Rathinaswamy, Manoj K.
Dalwadi, Udit
Fleming, Kaelin D.
Adams, Carson
Stariha, Jordan T. B.
Pardon, Els
Baek, Minkyung
Vadas, Oscar
DiMaio, Frank
Steyaert, Jan
Hansen, Scott D.
Yip, Calvin K.
Burke, John E.
author_sort Rathinaswamy, Manoj K.
collection PubMed
description The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-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 Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ–adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101–specific signaling events in vivo.
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spelling pubmed-83972742021-09-09 Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation Rathinaswamy, Manoj K. Dalwadi, Udit Fleming, Kaelin D. Adams, Carson Stariha, Jordan T. B. Pardon, Els Baek, Minkyung Vadas, Oscar DiMaio, Frank Steyaert, Jan Hansen, Scott D. Yip, Calvin K. Burke, John E. Sci Adv Research Articles The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-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 Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ–adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101–specific signaling events in vivo. American Association for the Advancement of Science 2021-08-27 /pmc/articles/PMC8397274/ /pubmed/34452907 http://dx.doi.org/10.1126/sciadv.abj4282 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Rathinaswamy, Manoj K.
Dalwadi, Udit
Fleming, Kaelin D.
Adams, Carson
Stariha, Jordan T. B.
Pardon, Els
Baek, Minkyung
Vadas, Oscar
DiMaio, Frank
Steyaert, Jan
Hansen, Scott D.
Yip, Calvin K.
Burke, John E.
Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title_full Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title_fullStr Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title_full_unstemmed Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title_short Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation
title_sort structure of the phosphoinositide 3-kinase (pi3k) p110γ-p101 complex reveals molecular mechanism of gpcr activation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397274/
https://www.ncbi.nlm.nih.gov/pubmed/34452907
http://dx.doi.org/10.1126/sciadv.abj4282
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