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Nov. 16, 2007 Research Highlight Biology

Unlocking the mysteries of a molecular motor

A combination of experimental and theoretical approaches may help explain the molecular mechanics underlying each muscle contraction

Image showing binding states of myosin and actin Figure 1: A proposed model for how changes in myosin’s interaction with actin filaments in the transition from the weakly bound state to the strongly bound state might translate into the mechanical movement necessary for muscle contraction. The breakdown of ATP and release of resulting byproducts at the motor domain (red, ocher and green regions) is translated to ratcheting of the lever arm (black) via a ‘converter’ domain (blue). © PNAS/ National Academy of Sciences/ 104/ 12718 (2007)

Flexing a muscle might seem like a smooth motion, but each contraction actually consists of several staged movements, as thin actin filaments slide along thick myosin filaments. Each thick filament consists of numerous myosin molecules that interact directly with actin. During contraction, these myosins consume adenosine triphosphate (ATP)—the fundamental energy currency of the cell—to generate a ratcheting motion that leads to direct mechanical movement of neighboring actin filaments.

The specific points of interaction between myosin and actin and the process by which myosin turns energy into movement have remained unclear, but Hirofumi Onishi of the RIKEN SPring-8 Center in Harima has made considerable progress in resolving some of these uncertainties. In recent studies conducted with Manuel Morales at the University of the Pacific in San Francisco, US—a former mentor and a longtime collaborator—Onishi’s group generated myosin mutants that revealed essential regions of the molecule. “Functional tests of these mutants allowed us to determine which residues are really responsible for the interaction between actin and myosin,” Onishi explains.

Now, Onishi and Morales have combined their findings with work from other researchers to develop a model that could help resolve the mysteries of myosin movement1. The two investigators compared two sets of structural data from different stages of actin–myosin interaction. The first was developed by Onishi and Morales to model the initial ‘weak’ association between myosin and actin, while the second was based on a structure representing the ‘strong’ interaction state observed after myosin has completed its movement.

Integrating these data with their mutational findings enabled Onishi and Morales to identify amino acids from myosin and actin involved in each step of the contraction process. This in turn led to a promising model for how physical movements triggered in the myosin head by ATP metabolism and changing interactions with the actin molecule in the transition from weak to strong binding might trigger mechanical activity elsewhere in the myosin molecule (Fig. 1).

“Comparison between these models was informative in clarifying the detailed mechanism of how influences initiated at the interface transmit to other functional sites,” says Onishi. This remains a theoretical model, and Onishi and Morales are planning to follow up with more sophisticated computer modeling and experimental strategies. “We have to investigate not only the actin-binding site,” he says, “but also other functional sites, in order to understand how myosin catalyzes ATP hydrolysis and delivers a mechanical impulse.”

References

  • 1. Onishi, H. & Morales, M.F. A closer look at energy transduction in muscle. Proceedings of the National Academy of Sciences USA 104, 12714–12719 (2007). doi: 10.1073/pnas.0705525104

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