Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Michigan, Ann Arbor
  • Purdue University
  • Temple University
  • Colorado State University

Details

Original languageEnglish (US)
Pages (from-to)15895-15900
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number32
StatusPublished - Aug 6 2019
Peer-reviewedYes

Abstract

G protein-coupled receptor (GPCR) kinases (GRKs) are responsible for initiating desensitization of activated GPCRs. GRK5 is potently inhibited by the calcium-sensing protein calmodulin (CaM), which leads to nuclear translocation of GRK5 and promotion of cardiac hypertrophy. Herein, we report the architecture of the Ca2+·CaM–GRK5 complex determined by small-angle X-ray scattering and negative-stain electron microscopy. Ca2+·CaM binds primarily to the small lobe of the kinase domain of GRK5 near elements critical for receptor interaction and membrane association, thereby inhibiting receptor phosphorylation while activating the kinase for phosphorylation of soluble substrates. To define the role of each lobe of Ca2+·CaM, we utilized the natural product malbrancheamide as a chemical probe to show that the C-terminal lobe of Ca2+·CaM regulates membrane binding while the N-terminal lobe regulates receptor phosphorylation and kinase domain activation. In cells, malbrancheamide attenuated GRK5 nuclear translocation and effectively blocked the hypertrophic response, demonstrating the utility of this natural product and its derivatives in probing Ca2+·CaM-dependent hypertrophy.

    Research areas

  • Calmodulin, G protein-coupled receptor kinase 5, Hypertrophy, Malbrancheamide

Citation formats

APA

Beyett, T. S., Fraley, A. E., Labudde, E., Patra, D., Coleman, R. C., Eguchi, A., ... Tesmer, J. J. G. (2019). Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe. Proceedings of the National Academy of Sciences of the United States of America, 116(32), 15895-15900. https://doi.org/10.1073/pnas.1818547116

Harvard

Beyett, TS, Fraley, AE, Labudde, E, Patra, D, Coleman, RC, Eguchi, A, Glukhova, A, Chen, Q, Williams, RM, Koch, WJ, Sherman, DH & Tesmer, JJG 2019, 'Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 32, pp. 15895-15900. https://doi.org/10.1073/pnas.1818547116