Adenosine Triphosphate

Do the twist

by David Bradley

Professor Kenneth Holmes FRS of the Max Planck Institute of Medical Research in Heidelberg, Germany, and colleagues have used advanced electron microscopy, to look closely at how the energy molecule adenosine triphosphate (ATP) controls the essential binding and release of the myosin crossbridge from the actin filament. After binding to actin, a lever arm on the rear of the crossbridge swings through an angle of about 60 degrees so pulling the thick filament past the thin filament. This is the power stroke during which adenosine diphosphate (ADP) is released. When ATP rebinds, the crossbridge quickly dissociates from actin, and the crossbridge is put back into its pre-power stroke state so a new cycle can start.


Holmes described how fitting atomic models to the electron microscopy results and a new crystal structure determination of the atomic coordinates of crossbridges from myosin V has allowed the researchers to see how strong binding of the myosin crossbridge to actin involves a change in the protein in which a deep cleft in one stretch of the protein closes. This in turn, Holmes explained, opens the binding pocket for ATP and enables ADP to be released. ATP binds more strongly than ADP and can reverse the process: it closes the nucleotide-binding pocket, which opens the cleft in the actin-binding site, leading to detachment from actin.

While this cleft closing works well in the model, Holmes went on to explain that there are problems with "steric" clashes, in which the various chemical groups are so over-crowded in the model that they simply could not sit comfortably together in real life. He explained that an alternative method of fitting has allowed the researchers to produce a model that avoids these clashes by invoking a twist in the central sheet-like portion of the protein. He pointed out that just such a twist has been found in the structure of myosin V.

The twist not only avoids steric crowding but relieves the tension on a kinked portion of the protein, allowing it straighten into its post-power stroke shape. The twisting of the central sheet may well be the mechanism whereby actin binding controls the power stroke, and so could be key to muscle contraction.


Read Part 1 - Muscle and Myosin