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Joseph RE, Lowe J, Fulton DB, et al. The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance. J Mol Biol. 2021;434(5):167422doi: 10.1016/j.jmb.2021.167422.
Joseph, R. E., Lowe, J., Fulton, D. B., Engen, J. R., Wales, T. E., & Andreotti, A. H. (2021). The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance. Journal of molecular biology, 434(5), 167422. https://doi.org/10.1016/j.jmb.2021.167422
Joseph, Raji E, et al. "The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance." Journal of molecular biology vol. 434,5 (2021): 167422. doi: https://doi.org/10.1016/j.jmb.2021.167422
Joseph RE, Lowe J, Fulton DB, Engen JR, Wales TE, Andreotti AH. The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance. J Mol Biol. 2021 Dec 23;434(5):167422. doi: 10.1016/j.jmb.2021.167422. Epub 2021 Dec 23. PMID: 34954235.
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J Mol Biol. 2021 Dec 23;434(5):167422. doi: 10.1016/j.jmb.2021.167422. Epub 2021 Dec 23.

The Conformational State of the BTK Substrate PLCγ Contributes to Ibrutinib Resistance.

Journal of molecular biology

Raji E Joseph, Jacques Lowe, D Bruce Fulton, John R Engen, Thomas E Wales, Amy H Andreotti

Affiliations

  1. Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
  2. Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: https://twitter.com/dbfulton.
  3. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: https://twitter.com/jrengen.
  4. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: [email protected].
  5. Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: [email protected].

PMID: 34954235 DOI: 10.1016/j.jmb.2021.167422

Abstract

Mutations in PLCγ, a substrate of the tyrosine kinase BTK, are often found in patients who develop resistance to the BTK inhibitor Ibrutinib. However, the mechanisms by which these PLCγ mutations cause Ibrutinib resistance are unclear. Under normal signaling conditions, BTK mediated phosphorylation of Y783 within the PLCγ cSH2-linker promotes the intramolecular association of this site with the adjacent cSH2 domain resulting in active PLCγ. Thus, the cSH2-linker region in the center of the regulatory gamma specific array (γSA) of PLCγ is a key feature controlling PLCγ activity. Even in the unphosphorylated state this linker exists in a conformational equilibrium between free and bound to the cSH2 domain. The position of this equilibrium is optimized within the properly regulated PLCγ enzyme but may be altered in the context of mutations. We therefore assessed the conformational status of four resistance associated mutations within the PLCγ γSA and find that they each alter the conformational equilibrium of the γSA leading to a shift toward active PLCγ. Interestingly, two distinct modes of mutation induced activation are revealed by this panel of Ibrutinib resistance mutations. These findings, along with the recently determined structure of fully autoinhibited PLCγ, provide new insight into the nature of the conformational change that occurs within the γSA regulatory region to affect PLCγ activation. Improving our mechanistic understanding of how B cell signaling escapes Ibrutinib treatment via mutations in PLCγ will aid in the development of strategies to counter drug resistance.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: HDX-MS; PLCγ; allostery; ibrutinib resistance; phospholipase C gamma

Conflict of interest statement

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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