PYK2 senses calcium through a disordered dimerization and calmodulin-binding element

Multidomain kinases use many ways to integrate and process diverse stimuli. Here, we investigated the mechanism by which the protein tyrosine kinase 2-beta (PYK2) functions as a sensor and effector of cellular calcium influx. We show that the linker between the PYK2 kinase and FAT domains (KFL) encompasses an unusual calmodulin (CaM) binding element. PYK2 KFL is disordered and engages CaM through an ensemble of transient binding events. Calcium increases the association by promoting structural changes in CaM that expose auxiliary interaction opportunities. KFL also forms fuzzy dimers, and dimerization is enhanced by CaM binding. As a monomer, however, KFL associates with the PYK2 FERM-kinase fragment. Thus, we identify a mechanism whereby calcium influx can promote PYK2 self-association, and hence kinase-activating trans-autophosphorylation. Collectively, our findings describe a flexible protein module that expands the paradigms for CaM binding and self-association, and their use for controlling kinase activity.

Momin, A. A., Mendes, T., Barthe, P., Faure, C., Hong, S., Yu, P., Kadaré, G., Jaremko, M., Girault, J.-A., Jaremko, Ł., & Arold, S. T. (2022). PYK2 senses calcium through a disordered dimerization and calmodulin-binding element. Communications Biology, 5(1).

We acknowledge SOLEIL for providing synchrotron radiation facilities (proposals nr. 20181104 and 20180576). We would also like to thank J. Perez and A. Thureau for assistance in using the beamline SWING. We thank the KAUST Bioscience, and Imaging and Characterisation core labs for their assistance. We thank T.M.D. Besong and O. Bakr from the Functional Nanomaterials Lab at KAUST for their help with the AUC measurement and analysis. We thank D. Renn and M. Rueping (KAUST Catalysis Center) for the access to the CD instrument. We also thank U.S. Hameed for discussions on the manuscript and R. Naser for help with NMR data. This publication is based on the work supported by the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under the Award Number URF/1/2602-01-01. The work in JAG’s lab was supported by grants from Agence Nationale de la Recherche (ANR-19-CE16-0020) and Fondation pour la Recherche Médicale (FRM, EQU201903007844). P.B. acknowledges support from the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05.

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