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

Abstract

Significance Bruton’s tyrosine kinase (Btk) activation on the cell membrane is critical for B cell proliferation and development, and Btk inhibition is a promising treatment for several hematologic cancers and autoimmune diseases. Here, we examine Btk activation using the results of long-timescale molecular dynamics simulations. In our simulations, Btk lipid-binding modules dimerized on the membrane in a single predominant conformation. We observed that the phospholipid PIP 3 —in addition to its expected role of recruiting Btk to the membrane—allosterically mediated dimer formation and stability by binding at two novel sites. Our results provide strong evidence that PIP 3 -mediated dimerization of Btk at the cell membrane is a critical step in Btk activation and suggest a potential approach to allosteric Btk inhibitor development.