Molecular Switches in Troponin

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Abstract
The contraction of vertebrate striated muscle contraction, and hence its work output, is controlled by Ca2+, which binds to troponin (Tn) associated with tropomyosin (TM) and actin in the thin filaments. Tn consists of three subunits: TnC, the Ca2+-receptor; TnI, an inhibitor of actomyosin activity; and TnT, anchoring Tn to T.M. Of the four Ca2+-binding sites, I and II in the N-terminal domain are Ca-specific sites, while sites III and IV, the high affinity Ca-Mg sites, are in the C-domain. The former are recognized as the functionally important triggering sites. TnC, whose structure has been solved by X-ray crystallography and recently by high-resolution NMR, contains two homologous globular domains connected by an unusual single α-helix. The C-terminal domain exhibits an open hydrophobic area regardless of whether Ca2+ or Mg2+ is bound to sites III and IV. In contrast, the N-terminal domain is a closed structure that opens a hydrophobic patch upon Ca2+-binding to its two “triggering” sites producing a TnI binding area. Crosslinking and fragment binding studies indicate that, in the main, the two polypeptide chains run in opposite directions in the complex of TnC with Tn. A model of TnC-TnI interactions based on low angle X-ray and neutron scattering is discussed in light of biochemical and other physico-chemical studies. The opening of the structure in the N-terminal domain of TnC may be regarded as a molecular switch. It activates a molecular switch in TnI, reflected in the movement of portions of its C-terminal half, including Cys l33, away from actin and closer to TnC, as well as other structural changes in Tnl. Finally the role of TnT in switching and transmitting the Ca2+-signal is discussed.