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Muscle Contraction
Andy Howard
Introductory Biochemistry
2 December 2008
Biochemistry: Muscles 12/02/2008
Chemistry of muscle
contraction
The most impressive movement
phenomenon in mesoscopic organisms is
muscle movement. It does have a
biochemical basis, which we’ll explore
today
Biochemistry: Muscles 12/02/2008 Page 2 of 46
What we’ll discuss
Skeletal muscle Dystrophin and
physiology cytoskeletal structure
Thin filaments: Coupling of ATP
actin, tropomyosin, hydrolysis to
troponin conformational
changes in myosin
Thick filaments:
Myosin & kinesin
myosin
Calcium channels and
Sliding filament troponin C
model
Smooth muscle
Biochemistry: Muscles 12/02/2008 Page 3 of 46
Essential Question
How can biological macromolecules,
carrying out conformational changes on
the microscopic, molecular level, achieve
these feats of movement that span the
molecular and macroscopic worlds?
We’ll look at the specifics of muscle
QuickTime™ an d a
contraction, which is an excellent example decompressor
are need ed to see this picture.
of this phenomenon
Note that Tom Irving, on our faculty, is a
world-recognized expert on muscle
physiology Prof. Thomas
C. Irving
Biochemistry: Muscles 12/02/2008 Page 4 of 46
Skeletal
Muscle
Cell
T-tubules
enable the
sarcolemmal
membrane to
contact the
ends of the
myofibril
Biochemistry: Muscles 12/02/2008 Page 5 of 46
What are t-tubules
and SR for?
The morphology is all geared to
Ca2+ release and uptake!
Nerve impulses reaching the muscle
produce an "action potential" that
spreads over the sarcolemmal
membrane and into the fiber along
the t-tubule network
Biochemistry: Muscles 12/02/2008 Page 6 of 46
t-tubules and SR, continued
The signal is passed across the
triad junction and induces
release of Ca2+ ions from the SR
Ca2+ ions bind to sites on the
fibers and induce contraction;
relaxation involves pumping the
Ca2+ back into the SR
Biochemistry: Muscles 12/02/2008 Page 7 of 46
Molecular mechanism of
contraction
Be able to explain the EM in Figure 16.12 in
terms of thin and thick filaments
Thin filaments are composed of actin polymers
F-actin helix is composed of G-actin monomers
F-actin helix has a pitch of 72 nm
But repeat distance is 36 nm
Actin filaments are decorated with tropomyosin
heterodimers and troponin complexes
Troponin complex consists of: troponin T (TnT),
troponin I (TnI), and troponin C (TnC)
Biochemistry: Muscles 12/02/2008 Page 8 of 46
Myo-
fibrils
Hexagonal
arrays
shown
(fig. 16.12)
Biochemistry: Muscles 12/02/2008 Page 9 of 46
Actin
monomer
One
domain
on each
side
(16.13)
Biochemistry: Muscles 12/02/2008 Page 10 of 46
Actin
helices
Pitch =
72nm
Repeat
= 36
nm
Fig.16.
14
Biochemistry: Muscles 12/02/2008 Page 11 of 46
Thin
filament
Tropomyosin coiled
coil winds around
the actin helix
Each TM dimer
interacts with 7
actin monomers
Troponin T binds to
TM at head-to-tail
junction
Biochemistry: Muscles 12/02/2008 Page 12 of 46
Composition & Structure of
Thick Filaments
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 are homologous to calmodulin
and also to TnC
See structure of heads in Figure 16.16
Biochemistry: Muscles 12/02/2008 Page 13 of 46
Myosin
Cartoon
EM
S1 myosin
head
structure
Biochemistry: Muscles 12/02/2008 Page 14 of 46
Repeating Structural Elements
Are the Secret of Myosin’s
Coiled Coils
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 seven-residue
repeat are hydrophobic; residues 2,3 and 6 (b, c
and f) are ionic
This repeating pattern favors formation of coiled
coil of tails. (With 3.6 - NOT 3.5 - residues per
turn, a-helices will coil!)
Biochemistry: Muscles 12/02/2008 Page 15 of 46
Axial view (fig. 16.17)
Myosin tail: 2-stranded a-helical coiled coil
Biochemistry: Muscles 12/02/2008 Page 16 of 46
More Myosin 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
Biochemistry: Muscles 12/02/2008 Page 17 of 46
Myosin packing
Adjoining molecules offset by ~ 14 nm
Corresponds to 98 residues of coiled coil
Biochemistry: Muscles 12/02/2008 Page 18 of 46
Associated proteins
of Muscle
a-Actinin, a protein that contains several
repeat units, forms dimers and contains
actin-binding regions, and is analogous in
some ways to dystrophin
Dystrophin is the protein product of the
first gene to be associated with muscular
dystrophy - actually Duchennes MD
See the box on pages 524-525
Biochemistry: Muscles 12/02/2008 Page 19 of 46
Dystrophin QuickTime™ an d a
decompressor
New Developments! are need ed to see this p icture .
Dystrophin is part of a large complex
of glycoproteins that bridges the
inner cytoskeleton (actin filaments)
and the extracellular matrix (via a Nick Menhart:
protein called laminin) BCPS faculty
Two subcomplexes: dystroglycan member
and sarcoglycan specializing in
dystrophin
Defects in these proteins have now research
been linked to other forms of
muscular dystrophy
Biochemistry: Muscles 12/02/2008 Page 20 of 46
Dystrophin, actinin,spectrin
Characteristic 3-helix regions
Biochemistry: Muscles 12/02/2008 Page 21 of 46
Spectrin-repeat
structure QuickTime™ an d a
decompressor
are need ed to see this p icture .
These
characteristic 3-
helix elements
are found in
actinin, spectrin, Spectrin repeat
dystrophin PDB 1AJ3
NMR
12.8 kDa
Biochemistry: Muscles 12/02/2008 Page 22 of 46
Model for
complex
Actin-dystrophin-
glycoprotein
complex
Dystrophin forms
tetramers of
antiparallel
monomers
Biochemistry: Muscles 12/02/2008 Page 23 of 46
The Dystrophin Complex
Links to disease
a-Dystroglycan - extracellular, binds to
merosin (a component of laminin) -
mutation in merosin linked to severe
congenital muscular dystrophy
-Dystroglycan - transmembrane protein
that binds dystrophin inside
Sarcoglycan complex - a, , - all
transmembrane - defects linked to limb-
girdle MD and autosomal recessive MD
Biochemistry: Muscles 12/02/2008 Page 24 of 46
Hugh Huxley
The Sliding QuickTime™ an d a
decompressor
Filament Model are need ed to see this picture.
Many contributors!
Hugh Huxley and Jean Hanson
Andrew Huxley and Ralph Niedergerke
Albert Szent-Györgyi showed that actin
and myosin associate (actomyosin
complex)
QuickTime™ an d a
decompressor
Sarcomeres decrease length during are need ed to see this p icture .
contraction (see Figure 16.19)
Szent-Gyorgyi also showed that ATP
causes the actomyosin complex to
dissociate Albert Szent-Györgyi
Biochemistry: Muscles 12/02/2008 Page 25 of 46
Sliding filaments
Decrease in sarcomere length happens because
of decreases in width of I band and H zone
No change in width of A band
Thin & thick filaments are sliding past one another
Biochemistry: Muscles 12/02/2008 Page 26 of 46
The Contraction Cycle
Study Figure 16.20!
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 ADP-free
state
Biochemistry: Muscles 12/02/2008 Page 27 of 46
Mechanism
Fig.
16.20
Biochemistry: Muscles 12/02/2008 Page 28 of 46
Actin-myosin
interaction Qui ckTi me™ and a
decompresso r
are ne eded to see thi s pi cture.
Ribbon- and space-
filling representations
Ivan Rayment
Qui ckTi me™ and a
decompresso r
are ne ede d to see thi s pi cture.
Hazel Holden
Biochemistry: Muscles 12/02/2008 Page 29 of 46
Similarities in
Motor Proteins
Initial events of myosin and
kinesin action are similar
But the conformational changes
that induce movement are
different in myosins, kinesins,
and dyneins
Biochemistry: Muscles 12/02/2008 Page 30 of 46
Myosin &
kinesin
motor
domains
Relay helix
moves back
and forth like
a piston
Biochemistry: Muscles 12/02/2008 Page 31 of 46
Intramolecular
communication &
conformational
changes
Myosin and kinesin:
ATP hydrolysis
conformational change
that gets communicated
to track-binding site
Dynein: not well
understood; involves
AAA ATPases
Biochemistry: Muscles 12/02/2008 Page 32 of 46
Muscle Contraction Is
Regulated by Ca2+
Ca2+ Channels and Pumps
Release of Ca2+ from the SR triggers
contraction
Reuptake of Ca2+ into SR relaxes muscle
So how is calcium released in response to
nerve impulses?
Answer has come from studies of
antagonist molecules that block Ca2+
channel activity
Biochemistry: Muscles 12/02/2008 Page 33 of 46
Ca2+ triggers
contraction
Release of Ca2+
through voltage- or
Ca2+-sensitive
channel activates
contraction
Pumps induce
relaxation
Biochemistry: Muscles 12/02/2008 Page 34 of 46
Dihydropyridine Receptor
In t-tubules of heart and skeletal muscle
Nifedipine and other DHP-like molecules
bind to the "DHP receptor" in t-tubules
In heart, DHP receptor is a voltage-gated
Ca2+ channel
In skeletal muscle, DHP receptor is
apparently a voltage-sensing protein and
probably undergoes voltage-dependent
conformational changes
Biochemistry: Muscles 12/02/2008 Page 35 of 46
Ryanodine Receptor
The "foot structure" in terminal cisternae of
SR
Foot structure is a Ca2+ channel of unusual
design
Conformation change or Ca2+ -channel
activity of DHP receptor apparently gates
the ryanodine receptor, opening and
closing Ca2+ channels
Many details are yet to be elucidated!
Biochemistry: Muscles 12/02/2008 Page 36 of 46
Ryanodine Receptor
Courtesy
BBRI QuickTime™ and a
decompressor
are neede d to see this picture.
Biochemistry: Muscles 12/02/2008 Page 37 of 46
Muscle Contraction Is
Regulated by Ca 2+
Tropomyosin and troponins mediate the
effects of Ca2+
See Figure 16.24
In absence of Ca2+, TnI binds to actin to
keep myosin off
TnI and TnT interact with tropomyosin to
keep tropomyosin away from the groove
between adjacent actins
But Ca2+ binding changes all this!
Biochemistry: Muscles 12/02/2008 Page 38 of 46
Ca 2+ Turns on Contraction
Binding of Ca2+ to TnC increases binding
of TnC to TnI, simultaneously decreasing
the interaction of TnI with actin
This allows tropomyosin to slide down into
the actin groove, exposing myosin-binding
sites on actin and initiating contraction
Since troponin complex interacts only with
every 7th actin, the conformational
changes must be cooperative
Biochemistry: Muscles 12/02/2008 Page 39 of 46
Thin & thick
filaments
Changes that
happen when
Ca2+ binds to
troponin C
Fig. 16.24
Biochemistry: Muscles 12/02/2008 Page 40 of 46
Binding of Ca 2+
to Troponin C
Four sites for Ca2+ on TnC - I, II, III and IV
Sites I & II are N-terminal; III and IV on C
term
Sites III and IV usually have Ca2+ bound
Sites I and II are empty in resting state
Rise of Ca2+ levels fills sites I and II
Conformation change facilitates binding of
TnC to TnI
Biochemistry: Muscles 12/02/2008 Page 41 of 46
2 views of
troponin C
Ribbon
Molecular
graphic
Fig. 16.25
Biochemistry: Muscles 12/02/2008 Page 42 of 46
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
Troponin C
Biochemistry: Muscles 12/02/2008 Page 43 of 46
Effect of hormones
on smooth muscle
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
Biochemistry: Muscles 12/02/2008 Page 44 of 46
Smooth Muscle Effectors
Useful drugs
Epinephrine (as Primatene) is an over-the-
counter 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
Biochemistry: Muscles 12/02/2008 Page 45 of 46
Oxytocin
structure
P.532
Biochemistry: Muscles 12/02/2008 Page 46 of 46
