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MUSCLE PROTEINS
• What is the mechanism whereby
conformational changes in biological
molecules is translated into macroscopic
movements?
Skeletal Muscle Anatomy
• A fiber bundle contains hundreds of myofibrils
that run the length of the fiber
• Each myofibril is a linear array of sarcomeres
• Each sarcomere is capped on ends by a transverse
tubule (t-tubule) that is an extension of
sarcolemmal membrane
• Surfaces of sarcomeres are covered by
sarcoplasmic reticulum containing calcium
16.1 What Is a Molecular Motor?
Figure 16.1 The structure of a skeletal
muscle cell, showing the manner in
which transverse tubules enable the
sarcolemmal membrane to extend into
the interior of the fiber.
Electron micrograph of a
skeletal muscle myofibril.
The length of one
sarcomere is indicated, as
are the A and I bands, the
H zone, the M disk, and
the Z lines. Cross-sections
from the H zone show a
hexagonal array of thick
filaments, whereas the I
band cross-section shows a
hexagonal array of thin
filaments. The major
chemical entities here are
F-actin and myosin.
The three-dimensional
structure of an actin
monomer from skeletal
muscle. This view shows
the two domains (left and
right) of actin. This
component in fibrillar
form, F-actin is the
material in the thinfillament potion of the
sarcomere.
The helical
arrangement of actin
monomers in F-actin.
The F-actin helix has a
pitch of 72 nm and a
repeat distance of 36
nm.
(a) An electron
micrograph of a thin
filament,
(b) a corresponding image
reconstruction, and
(c) a schematic drawing
based on the images in (a)
and (b).
The tropomyosin coiled
coil winds around the actin
helix, each tropomyosin
dimer interacting with
seven consecutive actin
monomers. Troponin T
binds to tropomyosin
The Composition and Structure of Thick
Filaments
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Myosin - 2 heavy chains, 4 light chains
Heavy chains - 230 kD each
Light chains - 2 pairs of different 20 kD chains
The "heads" of heavy chains have ATPase activity
and hydrolysis here drives contraction
Light chains regulate movement
(a) An electron micrograph of a
myosin molecule and a
corresponding schematic
drawing. The tail is a coiled coil
of intertwined a-helices
extending from the two globular
heads. One of each of the
myosin light chain proteins, LC1
and LC2, is bound to each of the
globular heads. Loss of the LC1
chain abolishes ATPase activity
of the myosin heads.
(b) A ribbon diagram shows the
structure of the S1 myosin head
(green, red, and purple
segments) and its associated
essential (yellow) and
regulatory (magenta) light
chains.
Repeating Structural Elements Are the
Secret of Myosin’s Coiled Coils
The secret to ultrastructure
• 7-residue, 28-residue and 196-residue repeats
are responsible for the organization of thick
filaments
• Residues 1 and 4 (a and d) of the sevenresidue repeat are hydrophobic; residues 2,3
and 6 (b, c and f) are ionic
• This repeating pattern favors formation of
coiled coil of tails.
Figure 16.17
An axial view of the two-stranded, a-helical coiled coil of a myosin tail. Hydrophobic residues a and d
(1 and 4)of the seven-residue repeat sequence align to form a hydrophobic core. Residues b, c, and f
(2,3 and 6) face the outer surface of the coiled coil and are typically ionic.
More Repeats!
• 28-residue repeat (4 x 7) consists of distinct
patterns of alternating side-chain charge (+ vs -),
and these regions pack with regions of opposite
charge on adjacent myosins to stabilize the
filament
• 196-residue repeat (7 x 28) pattern also
contributes to packing and stability of filaments
• Indeed, myosin molecules in the filament are
staggered relative to one another by 98 residues,
one-half the residue repeat
The packing of myosin molecules in a thick filament. Adjoining molecules are offset by
approximately 14 nm, a distance corresponding to 98 residues of the coiled coil.
Electron micrograph of a
skeletal muscle myofibril.
The length of one
sarcomere is indicated, as
are the A and I bands, the
H zone, the M disk, and
the Z lines. Cross-sections
from the H zone show a
hexagonal array of thick
filaments, whereas the I
band cross-section shows a
hexagonal array of thin
filaments. The major
chemical entities here are
F-actin and myosin.
DISPOSITION OF MUSCLE MOLECULES
IN ONE SARCOMERE
I a
H
a I
How does the system work? The sliding filament model of skeletal muscle contraction. The
decrease in sarcomere length is due to decreases in the width of the I band and H zone, with no
change in the width of the A band. These observations mean that the lengths of both the thick
and thin filaments do not change during contraction. Rather, the thick and thin filaments slide
along one another.
The Contraction Cycle: ATP Hydrolysis
Drives Conformation Changes in Myosin
Figure 16.9 The mechanism of skeletal muscle contraction. The
free energy of ATP hydrolysis drives a conformational change in
the myosin head, resulting in net movement of the myosin heads
along the actin filament.
The Contraction Cycle: ATP Hydrolysis
Drives Conformation Changes in Myosin
• Cross-bridge formation is followed by
power stroke with ADP and Pi release
• ATP binding causes dissociation of myosin
heads and reorientation of myosin head
• Details of the conformational change in
the myosin heads are coming to light
• Evidence now exists for a movement of at
least 35 Å in the conformation change
between the ADP-bound state and ADPfree state
Ca2+ is the trigger signal for muscle
contraction. Release of Ca2+ through voltageor Ca2+-sensitive channels activates
contraction. Ca2+ pumps induce relaxation by
reducing the concentration of Ca2+ available
to the muscle fibers.
A drawing of the thick and thin filaments of
skeletal muscle in cross-section showing the
changes that are postulated to occur when Ca2+
binds to troponin C.
Smooth Muscle Contraction
No troponin complex in smooth muscle
• In smooth muscle, Ca2+ activates myosin light chain
kinase (MLCK) which phosphorylates LC2, the
regulatory light chain of myosin
• Ca2+ effect is via calmodulin - a cousin of TnC
• Hormones regulate contraction - epinephrine, a
smooth muscle relaxer, activates adenylyl cyclase,
making cAMP, which activates protein kinase, which
phosphorylates MLCK, inactivating MLCK and
relaxing muscle
Smooth Muscle Effectors
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Useful drugs
Epinephrine (as Primatene) is an over-thecounter asthma drug, but it acts on heart as well
as on lungs - a possible problem!
Albuterol is a more selective smooth muscle
relaxer and acts more on lungs than heart
Albuterol is used to prevent premature labor
Oxytocin (pitocin) stimulates contraction of
uterine smooth muscle, inducing labor
Kinases and Phosphatases
• Kinases add a phosphate group to another
molecule from a donor such as ATP
• Phosphatases remove phosphate groups
• On proteins the presence of a phosphate
group on a serine/threonine/tyrosine –OH can
have regulatory implications (e.g. on myosin
light chains in smooth muscle).
Creatine Kinase and Phosphocreatine
Provide an Energy Reserve in Muscle
Figure 27.9 Phosphocreatine
serves as a reservoir of ATPsynthesizing potential.
Lactate Formed in Muscles is Recycled to
Glucose in the Liver
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How your liver helps you during exercise:
Recall that vigorous exercise can lead to a
buildup of lactate and NADH, due to oxygen
shortage and the need for more glycolysis
NADH can be reoxidized during the reduction of
pyruvate to lactate
Lactate is then returned to the liver, where it
can be reoxidized to pyruvate by liver LDH
Liver provides glucose to muscle for exercise
and then reprocesses lactate into new glucose
This is referred to as the Cori cycle (Figure 22.7)
Lactate Formed in Muscles is Recycled to
Glucose in the Liver
Figure 22.7 The
Cori cycle.
Muscle control by receptor agonism and antagonism
• Tropicamide, an antimuscarinic drug causes dilation
of the pupil by inhibiting the Acetylcholine receptors
of the circular muscles in the iris. Sympathomimetics
such as phenylephrine HCl are used to directly
stimulate the radial muscles of iris.