The native form of globular actin, G-actin, is formed in vivo as a result of complex post-translational folding processes that require ATP energy expenditure and are assisted by the 70 kDa heat shock protein, prefoldin and chaperonin containing TCP-1. G-actin is stabilized by the binding of one ATP molecule and one Ca(2+) ion (or Mg(2+) in vivo). Chemical denaturants, heating or Ca(2+) removal transform native actin (N) into 'inactivated actin' (I), a compact oligomer comprising 14-16 subunits. Viscogenic and crowding agents slow this process but do not stop it. The lack of calcium in the solution accelerates the spontaneous N → I transition. Thus, native G-actin has a kinetically stable (as a result of the high free energy barrier between the N and I states) but thermodynamically unstable structure, which, in the absence of Ca(2+) or other bivalent metal ions, spontaneously converts to the thermodynamically stable I state. It was noted that native actin has much in common with intrinsically disordered proteins: it has functionally important disordered regions; it is constantly in complex with one of its numerous partners; and it plays key roles in many cellular processes, in a manner similar to disordered hub proteins. By analyzing actin folding in vivo and unfolding in vitro, we advanced the hypothesis that proteins in a native state may have a thermodynamically unstable quasi-stationary structure. The kinetically stable native state of these proteins appears forcibly under the influence of intracellular folding machinery. The denaturation of such proteins is always irreversible because the inactivated state, for which the structure is determined by the amino acid sequence of a protein, comprises the thermodynamically stable state under physiological conditions.
Keywords: G-actin; globular proteins with quasi-stationary structure; inactivated actin; intrinsically disordered proteins; native actin.
© 2015 FEBS.