SECTION
2 1 .1
Muscle Systems
459
C terminus
FIGURE 21-4
Structure of /3-actin from a nonmuscle cell. As described in the text,
a -
and /i-actins are very similar. The shape is like a rectangular pillow, with
dimensions of roughly 5.5 x 5.5 x 3.5 nm, with a cleft in it. The U-shape
formed by this arrangement of the four major domains is stabilized by the
binding of Mg-ATP in the cleft, as shown. In the absence of bound
nucleotide, actin monomers denature readily. [From
M o le c u la r C ell
B io lo g y,
3rd ed., by Lodish et al. (Eds). W.H. Freeman, New York,
1995, p. 995.]
At concentrations exceeding 0.1 mM, ATP-G-actin
spontaneously polymerizes into filaments of F-actin in so-
lutions of physiological ionic strength and depolymerizes
at low ionic strength. Other structural or catalytic pro-
teins are not required. The bound ATP hydrolyzes during
polymerization but this is not an energy-requiring process;
Mg-ADP and hydrolysis-resistant ATP analogues also per-
mit polymerization, albeit at a slower rate. Each of the
four G-actin domains binds noncovalently with an adja-
cent G-actin, such that each G-actin is thought to interact
with four other G-actins in the growing filament. The four
interactin sites are specific, so that all of the G-actins as-
sembling into a filament have the same polarity, i.e., each
cleft points toward the same end of the filament. Thus,
one end of the filament has exposed I and III domains and
another has exposed II and IV domains, so that the whole
filament has a polarity. The affinities of the two ends for
new G-actin differ, so that in the normal range of cyto-
plasmic G-actin concentration (1 mM), actin polymerizes
5-10 times faster at one end of the filament [called the
(+) end] than at the other [(—) end]. Since the critical
concentration for polymerization is lower at the (+) end
(0.1 vs. 0.8 mM), it is possible for a filament to grow at one
end and shorten at the other. In most cases, capping pro-
teins prevent growth at one end so that the filament grows
only at the free end. In muscle, the (+) end is ultimately
capped by a protein (CapZ) which also binds to a-actinin
or other Z-disk proteins, and probably plays some role
in anchoring thin filaments to the Z-disk. The (—) end is
capped by an unrelated protein (tropomodulin) whose cap-
ping effectiveness is enhanced by tropomyosin. Thus, the
tropomodulin-capped (—) end extends toward the center
of the sarcomere on either side of the Z-disk.
G-actin is very highly conserved, both across actin
genes within a species and across species. Apparently, the
need for so many functional binding sites in a molecule
of that size leaves few options for nonlethal mutations.
Among the actins sequenced from 30 widely divergent
species, there were only 32 amino acid substitutions. One
implication of this is that when differences in contractile
properties are observed between various types of mus-
cle, those differences must be due to the motor protein
(myosin) or to the various regulatory proteins.
Thin filaments contain nebulin and two regulatory
proteins called
tropomyosin
and
troponin
(Figure 21-5).
Tropomyosin (M.W. 68,000) is a coiled-coil a-helical
FIGURE 21-5
Model of a thin filament. Two tropomyosin filaments, each composed of
two subfilaments, wind around the actin chain. They block the binding of
the globular heads of myosin molecules (in thick filaments) to the actin
molecules. Troponin consists of three polypeptides and binds to both actin
and tropomyosin.
