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

Publication date: Available online 31 July 2018Source: Biochimica et Biophysica Acta (BBA) - General SubjectsAuthor(s): Bin Sun, Erik C. Cook, Trever P. Creamer, Peter M. Kekenes-HuskeyAbstractCalcineurin (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 co-facilitate or hinder 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. Ou...

Source: Biochimica et Biophysica Acta (BBA) General Subjects - July 31, 2018 Category: Biochemistry Source Type: research