Tropomyosin and troponin cooperativity on the thin filament

The regulation of muscle contraction by the thin filament proteins tropomyosin (Tm) and troponin (Tn) has remained an area of interest since the proteins were first discovered 40 years ago.1,2 Although we have learnt a great deal about the proteins themselves and the mechanism by which they regulate muscle contraction some aspects of the mechanism remain to be adequately explained. Our interest is in the cooperativity of the calcium regulatory process and this remains poorly understood and several different models have been proposed. At it simplest the essence of the problem can be simply outlined. In skeletal muscle the binding of calcium to the two regulatory sites of TnC is required for activation of muscle contraction. Isolated TnC binds the calcium cooperatively, as might be expected for a two-calcium-ion switch, with a hill coefficient (h) of between 1 & 2.3,4 In contrast the calcium activation of isometric force in a skinned muscle fibre occurs with a much larger hill coefficient5,6 leading to the idea that cooperativity extends beyond the single actin7TmTn structural unit of the thin filament. Some models of muscle activation suggest the whole filament switches as a single unit while studies of the purified proteins in solution tend to indicate more limited cooperativity extending to only the nearest neighbour actin7TmTn units. In this paper the reasons why the nature of the cooperativity remains a problem will be explored together with an overview of what our recent studies of the proteins in solution have revealed about thin filament cooperativity.