Calcium binding to the thin filament protein troponin is required for cardiac and skeletal muscles to contract, and several studies indicate that this regulation involves shifting the tropomyosin position on the actin filament. When the regulatory sites of troponin do not have bound Ca 2ϩ , tropomyosin is located on the actin outer domain. In this position tropomyosin sterically interferes with much more of the myosin-binding site than it does in the presence of Ca 2ϩ , and therefore contraction is inhibited at low Ca 2ϩ concentrations. This regulatory scheme is supported by three-dimensional helical reconstructions of thin filaments examined by electron microscopy with negative staining (1, 2) or unstained in vitreous ice (3), and by modeling of x-ray diffraction patterns of muscle (4). Furthermore, it is consistent with the solution kinetics of myosin S1-thin filament binding in the absence of ATP (5). However, it is unclear how troponin affects the position of tropomyosin on actin, and more generally the inhibitory action of troponin is not well understood at a structural level, as opposed to better understandings of tropomyosin.Troponin consists of a relatively globular domain (including TnI 1 and TnC) and an elongated tail region, the NH 2 terminus of TnT (6, 7). The inhibitory actions of troponin have long been attributed to the TnI subunit. Skeletal muscle TnI inhibits the actin-myosin ATPase rate in the absence of the other troponin subunits TnC and TnT (8 -10), and this effect requires lower TnI concentrations in the presence rather than in the absence of tropomyosin (11). Cardiac TnI has similar properties, although the inhibition is less effective (12-14). The inhibitory effects of skeletal muscle TnI can be mimicked by the so-called inhibitory peptide, residues 96 -116 (10, 15), or identically by the corresponding cardiac peptide (14). The reversal of inhibition is related to Ca 2ϩ -dependent TnI-TnC interactions, elucidated in part at the atomic level (16). An additional TnI region, approximately 130 -150 residues, has also been implicated in inhibition (17)(18)(19). These and other data are consistent with an inhibitory mechanism consisting primarily of a TnI-actin interaction that is reversed by Ca 2ϩ , i.e. a localized actin-troponin interaction tethers the much longer tropomyosin on the actin outer domain in the absence, but not in the presence, of Ca 2ϩ . Indeed, our own electron microscope results show that Ca 2ϩ causes a decrease in troponin density in contact with actin (20). However, no high resolution data exists for these interactions, or for the assembled thin filament, and it remains possible that other mechanisms are also important for regulation and for determining the shifting positions of tropomyosin on the actin surface.This report describes new and unexpected attributes of the troponin tail, i.e. the NH 2 terminus of TnT. In the absence of all other portions of troponin, including TnI, cardiac TnT-(1-153) inhibited the interaction of myosin with actin-tropomyosin filaments. Helica...
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