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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
Descripción
Sumario: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.