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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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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. |
format | Online Article Text |
id | pubmed-6511029 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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