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Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane

Bruton’s tyrosine kinase (Btk) is critical for B cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspir...

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Detalles Bibliográficos
Autores principales: Wang, Qi, Pechersky, Yakov, Sagawa, Shiori, Pan, Albert C., Shaw, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511029/
https://www.ncbi.nlm.nih.gov/pubmed/31019091
http://dx.doi.org/10.1073/pnas.1819301116
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author Wang, Qi
Pechersky, Yakov
Sagawa, Shiori
Pan, Albert C.
Shaw, David E.
author_facet Wang, Qi
Pechersky, Yakov
Sagawa, Shiori
Pan, Albert C.
Shaw, David E.
author_sort Wang, Qi
collection PubMed
description Bruton’s tyrosine kinase (Btk) is critical for B cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspired by a previous suggestion that Btk activation might depend on dimerization of its lipid-binding PH–TH module on the cell membrane, we performed long-timescale molecular dynamics simulations of membrane-bound PH–TH modules and observed that they dimerized into a single predominant conformation. We found that the phospholipid PIP(3) stabilized the dimer allosterically by binding at multiple sites, and that the effects of PH–TH mutations on dimer stability were consistent with their known effects on Btk activity. Taken together, our simulation results strongly suggest that PIP(3)-mediated dimerization of Btk at the cell membrane is a critical step in Btk activation.
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spelling pubmed-65110292019-05-23 Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane Wang, Qi Pechersky, Yakov Sagawa, Shiori Pan, Albert C. Shaw, David E. Proc Natl Acad Sci U S A PNAS Plus Bruton’s tyrosine kinase (Btk) is critical for B cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspired by a previous suggestion that Btk activation might depend on dimerization of its lipid-binding PH–TH module on the cell membrane, we performed long-timescale molecular dynamics simulations of membrane-bound PH–TH modules and observed that they dimerized into a single predominant conformation. We found that the phospholipid PIP(3) stabilized the dimer allosterically by binding at multiple sites, and that the effects of PH–TH mutations on dimer stability were consistent with their known effects on Btk activity. Taken together, our simulation results strongly suggest that PIP(3)-mediated dimerization of Btk at the cell membrane is a critical step in Btk activation. National Academy of Sciences 2019-05-07 2019-04-24 /pmc/articles/PMC6511029/ /pubmed/31019091 http://dx.doi.org/10.1073/pnas.1819301116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Wang, Qi
Pechersky, Yakov
Sagawa, Shiori
Pan, Albert C.
Shaw, David E.
Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title_full Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title_fullStr Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title_full_unstemmed Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title_short Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
title_sort structural mechanism for bruton’s tyrosine kinase activation at the cell membrane
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511029/
https://www.ncbi.nlm.nih.gov/pubmed/31019091
http://dx.doi.org/10.1073/pnas.1819301116
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