Abstract
Phosphorylation of cardiac muscle troponin I by protein kinase A enhances troponin regulatory dynamics and is an essential part of the’ flight or fight’ response to adrenaline. Elucidating how phosphorylation at serines 22 and 23 modulates structural dynamics has been difficult as key regulatory segments of troponin are unresolved. The effect of phosphorylation on the wild type, obtained from all-atom molecular dynamics simulations of the troponin core, demonstrates a significant rigidification of the structure that involves a rearrangement of the cTnI(1-33) - cTnC interaction, and changes in the distribution of the cTnC helix A/B angle and the interdomain angle, between the regulatory head and ITC arm. The familiar dilated cardiomyopathy cTnC G159D mutation whose Ca2+-sensitivity is not modulated by cTnI phosphorylation exhibits a structure inherently more rigid than WT, with phosphorylation reversing the direction of all metrics relative to WT.
Supplementary materials
Title
Supplementary data for Modulation of structure and dynamics of cardiac troponin by phosphorylation and mutations revealed by molecular dynamics simulations
Description
Additional figures, weblinks embedded for all data used in the paper, PDB's of structures and movies
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