4.7 Article

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

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COMMUNICATIONS BIOLOGY
卷 5, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s42003-022-03760-8

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  1. King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) [URF/1/2602-01-01]
  2. Agence Nationale de la Recherche [ANR-19-CE16-0020]
  3. Fondation pour la Recherche Medicale (FRM) [EQU201903007844]
  4. French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05]
  5. Agence Nationale de la Recherche (ANR) [ANR-19-CE16-0020] Funding Source: Agence Nationale de la Recherche (ANR)

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This study investigates the mechanism of how PYK2 functions as a sensor and effector of cellular calcium influx. It identifies a calmodulin binding element in the linker between the PYK2 kinase and FAT domains. The results show that calcium influx promotes PYK2 self-association, leading to kinase activation.
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. Protein tyrosine kinase 2-beta is shown to function as a sensor and effector of cellular calcium influx through self-association.

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