chapter 21
Muscle and Nonmuscle Contractile Systems
register, and play an important role in transmitting force
produced in the myofibrils to adjacent myofibrils and, via
the costamere structure, to the extracellular matrix. It ap-
pears that this mechanism of force transmission, rather
than transmission across the tapered ends of the cells, is
the major means of force transmission from myofibril to
Between the Z-disks, other regularly recurring features
are seen (Figure 21-3). Each complete filament assembly,
from one Z-disk to the next, is called a sarcomere, and is
the basic structural and functional unit of the fibril. The
A-band corresponds to the bundle of thick filaments cen-
tered between Z-disks, while the I-band is the region on
either side of a Z-disk that contains only thin filaments.
Thick and thin filaments partially overlap, making the
A-band darker at its ends and leaving a light area in the
middle where there is no overlap. A clue to the mechanism
of contraction was the finding that during contraction, the
H- and I-bands shorten, while the A-bands do not.
In the center of the A-band, the thick filaments are
linked by a network of proteins forming the M-line. The
pattern of cross-linking of these proteins, such as my-
omesin, and their ability to bind the thick filament protein
myosin probably explains the hexagonal arrangement of
the thick filaments. Cytosolic creatine kinase activity also
localizes extensively to the M-line region and may actually
be a property of one of the myosin cross-linking M-line
Another set of filaments, sometimes called the “third
filament system,” helps maintain sarcomere structure. A
very long protein
holds the thick filament array
centered in the sarcomere. Titin is an enormous pro-
tein consisting of more than 27,000 amino acids with
a M.W. of about 3 million Da. One end binds to one
or more M-line proteins and the other binds to one or
more proteins in the Z-disk. Most of the molecule com-
prises repeats of large domains resembling fibronectin 3
(FN3) and immunoglobulin. There is a super-repeat of
these motifs occurring 11 times within the A-band re-
gion of the molecule, which suggests a functional rela-
tionship with a group of thick filament accessory pro-
teins that occur in 11 bands in each half of the A-band.
Thus, there may be multiple attachments of titin to thick
There are also globular regions of the molecule located
between the thick filaments and the Z-disk, which appar-
ently unravel one by one as increasing tension is applied
to the molecule; these fold back into globules as tension is
released. This region of titin is like a long spring capable of
considerable elongation before reaching its elastic limit. In
cardiac muscle, which has a low compliance, this region of
titin contains only 163 amino acids, while in soleus muscle
(whose compliance is 10 times that of cardiac muscle), it is
over 2000 amino acids long. It appears that passive tension
in muscle is accounted for by the myofibrillar structure in-
side the fiber, not the connective network outside it, and
titin is probably the main structural protein involved.
Another very long protein (
) is associated with
the thin filaments. Nebulin has a molecular weight of about
700,000. An abundant protein in skeletal muscle, nebu-
lin extends from either side of the Z-disks along the en-
tire length of the thin filaments. It may serve as a tem-
plate for thin-filament assembly, and may interact with
tropomyosin, and also may have a regulatory role.
Thin Myofilaments
Thin myofilaments are polymers of globular (G) actin
molecules (M.W. 42,000). Although the actin gene has
apparently undergone considerable duplication, only six
actin genes are expressed in mammals; three are a-actins,
which are the actins found in sarcomeric thin filaments,
each in a different type of muscle. These actins are
375 amino acids long; the ones found in skeletal and car-
diac muscle have valine at position 17, unlike all others.
There are also two y-actins and one /J-actin. The /3-actin
and one of the y-actins are cytoskeletal actins found in
almost all nonmuscle cells. They lack the N-terminal as-
partate of skeletal muscle actin and have 374 amino acids.
The N-terminal residue of G-actin is always acetylated,
and typically some of these are sequentially removed as
part of the posttranslational modifications common in the
N-terminal region. The other y-actin seems to be ex-
pressed only in gut smooth muscle. For all six, essential
amino acids (especially leucine, isoleucine, and threonine)
account for about 41% of the molecule. Skeletal G-actin
contains N3-methylhistidine as does myosin. Other pro-
teins contain methylhistidine (e.g., acetylcholinesterase),
but in quantitatively insignificant amounts compared to
actin and myosin. Consequently, urinary methylhistidine
excretion has been used as a marker for contractile protein
turnover and as an indirect indicator of muscle mass.
G-actin has four globular domains (arranged in a
U-shape) designated domains I through IV with a cleft
between domains II and IV (Figure 21-4). This structure
is stabilized by the binding of Mg-ATP in the cleft (called
an ATPase fold) by ionic and hydrogen bonds between
the Mg-ATP and adjacent amino acid side chains. Several
other ATP-binding proteins (e.g., hexokinase) have been
found to have similar ATPase folds in which the bottom
of the cleft acts as a hinge region allowing the cleft to be
bent open. Binding of Mg-ATP (or Mg-ADP) holds the
cleft closed and stabilizes the molecule. Without bound
nucleotide, actin denatures readily.
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