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The Ca-sensitive regulatory switch of cardiac muscle is a paradigmaticexample of protein assemblies that communicate ligand binding throughallosteric change. The switch is a dimeric complex of troponin C (TnC), anallosteric sensor for Ca, and troponin I (TnI), an allosteric reporter.Time-resolved equilibrium FRET measurements suggest that the switch activatesin two steps: a TnI-independent Ca-priming step followed by TnI-dependentopening. To resolve the mechanistic role of TnI in activation we performedstopped-flow FRET measurements of activation following rapid addition of alacking component (Ca or TnI) and deactivation following rapid chelation of Ca.The time-resolved measurements, stopped-flow measurements, and Ca-titrationmeasurements were globally analyzed in terms of a new quantitative dynamicmodel of TnC-TnI allostery. The analysis provided a mesoscopic parameterizationof distance changes, free energy changes, and transition rates among theaccessible coarse-grained states of the system. The results reveal (i) theCa-induced priming step, which precedes opening, is the rate limiting step inactivation, (ii) closing is the rate limiting step in deactivation, (iii) TnIinduces opening, (iv) an incompletely deactivated population when regulatory Cais not bound, which generates an accessory pathway of activation, and (v)incomplete activation by Ca--when regulatory Ca is bound, a 3:2 mixture ofdynamically inter-converting open (active) and primed-closed (partially active)conformers is observed (15 C). Temperature-dependent stopped-flow FRETexperiments provide a near complete thermo-kinetic parametrization of opening.<Abstract Truncated>

The cardiac Ca-sensitive regulatory switch, a system in dynamic equilibrium