Structural Dynamics of Troponin I during Ca2+-Activation of Cardiac Thin Filaments: A Multi-Site Förster Resonance Energy Transfer Study

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Abstract

A multi-site, steady-state Forster resonance energy transfer (FRET) approach was used to quantify Ca(2+)-induced changes in proximity between donor loci on human cardiac troponin I (cTnI), and acceptor loci on human cardiac tropomyosin (cTm) and F-actin within functional thin filaments. A fluorescent donor probe was introduced to unique and key cysteine residues on the C- and N-termini of cTnI. A FRET acceptor probe was introduced to one of three sites located on the inner or outer domain of F-actin, namely Cys-374 and the phalloidin-binding site on F-actin, and Cys-190 of cTm. Unlike earlier FRET analyses of protein dynamics within the thin filament, this study considered the effects of non-random distribution of dipoles for the donor and acceptor probes. The major conclusion drawn from this study is that Ca(2+) and myosin S1-binding to the thin filament results in movement of the C-terminal domain of cTnI from the outer domain of F-actin towards the inner domain, which is associated with the myosin-binding. A hinge-linkage model is used to best-describe the finding of a Ca(2+)-induced movement of the C-terminus of cTnI with a stationary N-terminus. This dynamic model of the activation of the thin filament is discussed in the context of other structural and biochemical studies on normal and mutant cTnI found in hypertrophic cardiomyopathies.

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Wang, H., Chalovich, J. M., & Marriott, G. (2012). Structural Dynamics of Troponin I during Ca2+-Activation of Cardiac Thin Filaments: A Multi-Site Förster Resonance Energy Transfer Study. PLoS ONE, 7(12). https://doi.org/10.1371/journal.pone.0050420

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