CH16 Cytoskeleton.pdf - finedrafts

1030 Chapter 16:The Cytoskeleton
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tropon in
comPlex tropomvosin
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ca2*
myosin-binding site exposed
by Ca'*-mediated tropomyosin
movement
Figure 16-78 The control of skeletal muscle contraction by troponin. (A) A skeletal muscle cell thin filament, showing the
positions of tropomyosin and troponin along the actin filament. Each tropomyosin molecule has seven evenly spaced
regions with similar amino acid sequences, each of which is thought to bind to an actin subunit in the filament.
(B) A thin filament shown end-on, illustrating how Ca2+ (binding to troponin) is thought to relieve the tropomyosin
blockage of the interaction between actin and the myosin head. (A, adapted from G.N. Phillips, J.P. Fillers and C. Cohen,
J. Mol. Biol. 192:111-131,1986. With permission from Academic Press.)
myosin heads, thereby preventing any force-generating interaction. \Mhen the
level of Ca2* is raised, troponin C-which binds up to four molecules of Caz+causes
troponin I to release its hold on actin. This allows the tropomyosin
molecules to slip back into their normal position so that the myosin heads can
walk along the actin filaments (Figure f 6-78). Troponin C is closely related to
the ubiquitous Caz*-binding protein calmodulin (see Figure lS=44); it can be
thought of as a specialized form of calmodulin that has acquired binding sites
for troponin I and troponin ! thereby ensuring that the myofibril responds
extremely rapidly to an increase in Ca2+ concentration.
In smooth muscle cells, so-called because they lack the regular striations of
skeletal muscle, contraction is also triggered by an influx of calcium ions, but the
regulatory mechanism is different. Smooth muscle forms the contractile portion
of the stomach, intestine, and uterus, the walls of arteries, and many other structures
requiring slow and sustained contractions. smooth muscle is composed of
sheets of highly elongated spindle-shaped cells, each with a single nucleus.
Smooth muscle cells do not express the troponins. Instead, Caz* influx into the
cell regulates contraction by two mechanisms that depend on the ubiquitous
calcium binding protein calmodulin.
First, Ca2+-bound calmodulin binds to an actin-binding protein, caldesmon,
which blocks the actin sites where the myosin motor heads would normally
bind. This causes the caldesmon to fall off of the actin filaments, preparing the
filaments for contraction. Second, smooth muscle myosin is phosphorylated on
one of its two light chains by myosin light chain kinase (MLCK.), as described
previously for regulation of nonmuscle myosin II (see Figure 16-72).lVhen the
light chain is phosphorylated, the myosin head can interact with actin filaments
and cause contraction; when it is dephosphorylated, the myosin head tends to
dissociate from actin and becomes inactive (in contrast to nonmuscle myosin II,
light chain dephosphorylation does not cause thick filament disassembly in
smooth muscle cells). MLCK requires bound ca2*/calmodulin to be fully active.
External signaling molecules such as adrenaline (epinephrine) can also regulate
the contractile activity of smooth muscle. Adrenaline binding to its G-protein-coupled
cell surface receptor causes an increase in the intracellular level of
cyclic AMf; which in turn activates cyclic-AMP-dependent protein kinase (pKA)
(see Figure l5-35). PKA phosphorylates and inactivates MLCK, thereby causing
the smooth muscle cell to relax.
The phosphorylation events that regulate contraction in smooth muscle
cells occur realtively slowly, so that maximum contraction often requires nearly
a second (compared with the few milliseconds required for contraction of a
skeletal muscle cell). But rapid activation of contraction is not important in
smooth muscle: its myosin II hydrolyzes ArP about l0 times more slowly than
skeletal muscle myosin, producing a slow cycle of myosin conformational
changes that results in slow contraction.