section 21.2
Mechanism of Muscle Contraction: Overview
F IG U R E 2 1 -1 0
Schematic illustration of the sliding filament-rotating head mechanism of
force generation in muscle. Cross-bridges form approximately at right
angles to the thin filaments (a). This angle changes to about 45 degrees at
the end of the cross-bridge cycle when the bridge is released. Recent
measurements indicate that the initial and final angles in intact sliding
filaments are more nearly 80 and 50°, respectively. In the attached bridge, a
conformational change occurs, putting tension on the neck region. This
may be due to an abrupt change in the angle of the head (b). Movement of
the thick and thin filaments relative to each other relieves the stress on the
neck. The product of the tension (force) and the distance moved is the work
done per stroke by a cross-bridge.
as that actually observed for binding of myosin to actin.
This suggests the capture of energy internally in the
myosin head, actin, or both. Apparently, as the myosin
moves into this tightly bound configuration, energy is cap-
tured in the form of deformation within the myosin head,
which applies force (5-10 piconewtons) to the head’s at-
tachment to the thick filament (the neck region). Much,
probably most, of this energy is available to do mechan-
ical work as the filaments slide past one another (the
power stroke illustrated schematically in Figure 21-10),
with myosin ending up very firmly bound to actin. Sub-
sequent binding of Mg-ATP to myosin, which is also a
very high-affinity binding, provides the free-energy input
to the system to alter myosin’s actin binding site to a low-
affinity state, permitting detachment. ATP binding lowers
the affinity of myosin for actin by a factor of about
1 0
Hydrolysis of the ATP then occurs, with little change in
the free energy of the system. Subsequent events release
Pi and ADP from the ATPase site.
Thus, in the cross-bridge cycle, myosin is bound with
high affinity alternately to actin and to ATP. Since the
energy changes associated with myosin binding to actin
and MgATP are internal to the system, the only free energy
changes externally observable are the free-energy change
from ATP in solution to ADP and P; in solution, which
equals the sum of the mechanical work performed plus
the heat released. Thus the overall result is the conversion
of energy of hydrolysis of ATP (about 50 kJ/mol under
physiological conditions) to work (and heat), a process
chemomechanical transduction.
The efficiency of
this process in mammalian skeletal muscle is 60-70%.
There is uncertainty over the timing of ATP hydrol-
ysis and release of ADP and Pi with respect to the ac-
tomyosin binding states and the power stroke. It is cur-
rently thought that ATP hydrolysis occurs after transition
of the actomyosin-ATP (A-M-ATP) complex to a weakly-
bound state and may sometimes occur after release of
myosin from actin. The complex A-M-ADP-P; may re-
main weakly bound until dislodged by movement of the
filaments. The released M-ADP-P; has moderate affinity
for actin, and upon reattachment, forming A-M-ADP-Pj,
the phosphate release step occurs. This creates a state
called A-M*-ADP which is the high-affinity state asso-
ciated with initiating the power stroke. As the structural
changes produced by increasingly tight binding to actin
produce strain in the myosin head and therefor force and
movement, the affinity of the ATPase site for ADP also
changes, releasing the ADP. Thus, at the end of the power
stroke, cross-bridges are typically in the A-M state (called
the rigor state), their most tightly bound rigid state, in
which they will remain unless ATP is available to bind to
the ATPase site and alter the affinity of the actin binding
site (Figure 21-11). In normal circumstances it is almost
impossible to deplete ATP to the point that a large propor-
tion of myosin heads form rigor bonds, but it does hap-
pen in severely ischemic muscle and post-mortem (rigor
mortis). When Mg-ATP is available, binding occurs and
alters the actin binding site to a low-affinity configura-
tion, and hydrolysis follows, so that the cross-bridge will
probably be in the weakly-bound A-M-ADP-P; state until
once again pulled free. So long as [Ca2+]i remains high,
this cycle will continue, provided that adequate ATP con-
centration and other appropriate conditions of the internal
environment are maintained. The rate-limiting step is the
P; release step, and all of the steps following P, release
up through ATP hydrolysis happen quickly, so that the
M-ADP-P; and A-M-ADP-P; states predominate.
In a general way, transport ATPases are similar to
myosin. The initial binding of the transported substance
to the transport protein corresponds to tight binding of
myosin to actin. Reorientation of the binding site to-
ward the opposite face of the membrane is analogous to
the force-producing conformational change in the myosin
head, and conversion of the substrate binding site to a
low-affinity state is accomplished by binding of ATP. ATP
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