Tropomyosin (Tm) is most widely known for its role in muscle contraction; its calcium-dependent cooperation with the troponin complex in regulating the interaction of myosin and actin required to generate the power stroke within the sarcomeres of muscle cells. Tm is expressed in all eukaryotic cell types in more than 40 isoforms that are widely distributed within individual cells. Consequently, Tm plays a critical role in numerous biologically relevant processes and is associated with several diseases, including cardiomyopathy and cancer.
Tm is a two-stranded α-helical coiled-coil of 284-residues per polypeptide chain. How signals are transmitted along this rod-like molecule of more than 400 Ao remains a major challenge for protein chemists. We made the first identification of a stability control region (SCR) residues 97-118 in the 284-residue tropomyosin sequence that controls overall protein stability but is not required for folding. We have shown that a single mutation L110A destabilizes the entire Tm (1-131) molecule, showing that the effect of this mutation is transmitted 165 Ao along the coiled-coil in the N-terminal direction. The single mutation A109L prevents the SCR from transmitting stabilizing information and separates the coiled-coil into two domains, one that is ~9oC more stable than wild type and one that is ~16oC less stable. Learning how stability information is transmitted along rod-like molecules is crucial to understanding function and signaling.
Selected publications are listed.
Kirwan, J.P. and R.S. Hodges. Transmission of stability information through the N-domain of tropomyosin is interrupted by a stabilizing mutation (A109L) in the hydrophobic core of the stability control region (97-118). J. Biol. Chem. 389: 4356-4366 (2014).
Kirwan, J.P. and R.S. Hodges. Critical interactions in the stability control region of tropomyosin. J. Structural Biology 170: 294-306 (2010). PMC2856757 PMID20144718
Hodges, R.S., J. Mills, S. McReynolds, J.P. Kirwan, B. Tripet, and D. Osguthorpe. Identification of a unique “stability control region” that controls protein stability of tropomyosin: a two-stranded a-helical coiled-coil. J. Mol. Biol. 392: 747-762 (2009). PMC2756485 PMID19627992
Kwok, S.C. and R.S. Hodges. Stabilizing and Destabilizing Clusters in the Hydrophobic Core of Long Two-stranded a-Helical Coiled-Coils. J. Biol. Chem. 279: 21576-21588 (2004).