Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

Chung, Jean K.; Nocka, Laura M.; Decker, Aubrianna; Wang, Qi; Kadlecek, Theresa A.; Weiss, Arthur; Kuriyan, John; Groves, Jay T.

doi:10.1073/pnas.1819309116

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

Journal Article · Fri May 10 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1819309116· OSTI ID:1561917

Chung, Jean K. ^[1]; Nocka, Laura M. ^[1]; Decker, Aubrianna ^[1]; Wang, Qi ^[1]; Kadlecek, Theresa A. ^[2]; Weiss, Arthur ^[2]; Kuriyan, John ^[1]; Groves, Jay T. ^[3]

Univ. of California, Berkeley, CA (United States)
Univ. of California, San Francisco, CA (United States)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

The transformation of molecular binding events into cellular decisions is the basis of most biological signal transduction. A fundamental challenge faced by these systems is that reliance on protein–ligand chemical affinities alone generally results in poor sensitivity to ligand concentration, endangering the system to error. Here, we examine the lipid-binding pleckstrin homology and Tec homology (PH-TH) module of Bruton’s tyrosine kinase (Btk). Using fluorescence correlation spectroscopy (FCS) and membrane-binding kinetic measurements, we identify a phosphatidylinositol (3–5)-trisphosphate (PIP₃) sensing mechanism that achieves switch-like sensitivity to PIP₃levels, surpassing the intrinsic affinity discrimination of PIP₃:PH binding. This mechanism employs multiple PIP₃binding as well as dimerization of Btk on the membrane surface. Studies in live cells confirm that mutations at the dimer interface and peripheral site produce effects comparable to that of the kinase-dead Btk in vivo. These results demonstrate how a single protein module can institute an allosteric counting mechanism to achieve high-precision discrimination of ligand concentration. Furthermore, this activation mechanism distinguishes Btk from other Tec family member kinases, Tec and Itk, which we show are not capable of dimerization through their PH-TH modules. This suggests that Btk plays a critical role in the stringency of the B cell response, whereas T cells rely on other mechanisms to achieve stringency.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institute of Health

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1561917

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 22 Vol. 116; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

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