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