Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin.

Autor: Sun B; Department of Chemistry, University of Kentucky, 505 Rose St., Chemistry-Physics Building, Lexington, KY, USA 40506., Cook EC; Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone, St. Lexington, KY, USA 40536., Creamer TP; Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone, St. Lexington, KY, USA 40536., Kekenes-Huskey PM; Department of Chemistry, University of Kentucky, 505 Rose St., Chemistry-Physics Building, Lexington, KY, USA 40506. Electronic address: pkekeneshuskey@uky.edu.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. General subjects [Biochim Biophys Acta Gen Subj] 2018 Dec; Vol. 1862 (12), pp. 2651-2659. Date of Electronic Publication: 2018 Jul 31.
DOI: 10.1016/j.bbagen.2018.07.027
Abstrakt: Calcineurin (CaN) is a serine/threonine phosphatase that regulates a variety of physiological and pathophysiological processes in mammalian tissue. The calcineurin (CaN) regulatory domain (RD) is responsible for regulating the enzyme's phosphatase activity, and is believed to be highly-disordered when inhibiting CaN, but undergoes a disorder-to-order transition upon diffusion-limited binding with the regulatory protein calmodulin (CaM). The prevalence of polar and charged amino acids in the regulatory domain (RD) suggests electrostatic interactions are involved in mediating calmodulin (CaM) binding, yet the lack of atomistic-resolution data for the bound complex has stymied efforts to probe how the RD sequence controls its conformational ensemble and long-range attractions contribute to target protein binding. In the present study, we investigated via computational modeling the extent to which electrostatics and structural disorder facilitate CaM/CaN association kinetics. Specifically, we examined several RD constructs that contain the CaM binding region (CAMBR) to characterize the roles of electrostatics versus conformational diversity in controlling diffusion-limited association rates, via microsecond-scale molecular dynamics (MD) and Brownian dynamic (BD) simulations. Our results indicate that the RD amino acid composition and sequence length influence both the dynamic availability of conformations amenable to CaM binding, as well as long-range electrostatic interactions to steer association. These findings provide intriguing insight into the interplay between conformational diversity and electrostatically-driven protein-protein association involving CaN, which are likely to extend to wide-ranging diffusion-limited processes regulated by intrinsically-disordered proteins.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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