In this week’s on-line issue of the Proceedings of the National Academy of Sciences (PNAS), Brandeis researchers Jerry H. Brown, V. S. Senthil Kumar, Elizabeth O’Neall-Hennessey, Ludmila Reshetnikova, and Michelle Nguyen-McCarty ’10, together with Professors Andrew Szent-Györgyi and Carolyn Cohen, and Brookhaven National Laboratory researcher Howard Robinson, reveal the existence of a pair of major new hinges in the muscle protein myosin.
Muscle consists of myosin-containing thick filaments with projections, i.e. myosin heads, that exert force on actin-containing thin filaments during contraction. Previous crystal structures of the myosin head from bay scallop striated muscles and vertebrate muscles have already shown how this motion is produced by the amplification of small conformational changes about hinges in the motor domain (MD) by the so-called lever arm, which consists of the converter and elongated light chain binding domain (LCD). Just like a baseball bat or other lever arms we are all familiar with in the “real world”, this LCD of myosin has appeared to be relatively rigid in these crystal structures, as it needs to be to transmit force effectively. But it has also long been expected that in muscle the myosin head, including its lever arm, is likely to contain elastic elements so that force can be produced under various strains.
(Left) Schematic of a myosin molecule and (right) the two conformations of the heavy chain portion of the LCD.
The Brandeis researchers originally set out to crystallize a myosin LCD corresponding to that from the catch muscle of sea scallop because it contains a specialized sequence whose structure was predicted to give insight into how muscle contraction of smooth muscles is turned on and off. Remarkably, however, as described in the PNAS article, this LCD forms two different conformations in the crystal, about mechanically linked hinges in the part of the lever arm distal from the motor. For the first time — and quite unexpectedly— a potential major elastic element in the lever arm has been visualized at atomic resolution, one that allows the length of the lever arm to change by about 10%. Sequence comparisons strongly suggest that these specific hinges are likely to be found in the lever arms of all muscle myosins. These comparisons also indicate differences in the degree of flexibility about these hinges in the different myosins, perhaps helping to account for the different properties (e.g., speed of contraction) of different types of muscle.
This result may also be important for mechanical engineers. In 2009, one of the authors (JHB) wrote an article in American Scientist that expands the concept of biomimicry by describing potentially novel joints, switches, and other mechanical designs that can be derived from the structures of various proteins. The current results in the PNAS seem to add one more. As described by Olena Pylypenko and former Brandeis researcher Anne Houdusse in a commentary scheduled to accompany the print version of the PNAS article, the motion about the hinge of the myosin LCD resembles the motion of a foot relative to a leg about an ankle. A lever “arm” that can extend or compress about an “ankle” may thus be one more novel mechanical design that nature can teach us about.
Science at Brandeis 