Contraction of Skeletal Muscles. Physiologic Anatomy of Skeletal Muscle.
12/02/2008Biochemistry: Muscles Muscle Contraction Andy Howard Introductory Biochemistry 2 December...
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12/02/2008Biochemistry: Muscles
Muscle Contraction
Andy HowardIntroductory Biochemistry
2 December 2008
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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
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What we’ll discuss Skeletal muscle physiology
Thin filaments: actin, tropomyosin, troponin
Thick filaments: myosin
Sliding filament model
Dystrophin and cytoskeletal structure
Coupling of ATP hydrolysis to conformational changes in myosin
Myosin & kinesin Calcium channels and troponin C
Smooth muscle
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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 contraction, which is an excellent example of this phenomenon
Note that Tom Irving, on our faculty, is a world-recognized expert on muscle physiology
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Prof. Thomas C. Irving
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Skeletal Muscle Cell
T-tubules enable the sarcolemmal membrane to contact the ends of the myofibril
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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
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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
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Molecular mechanism of contractionBe 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)
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Myo- fibrils
Hexagonal arrays shown(fig. 16.12)
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Actin monomer
One domain on each side(16.13)
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Actin helices Pitch = 72nm
Repeat = 36 nm
Fig.16.14
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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
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Composition & Structure of Thick FilamentsMyosin - 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
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Myosin Cartoon EM S1 myosin head structure
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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, -helices will coil!)
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Axial view (fig. 16.17)Myosin tail: 2-stranded -helical coiled coil
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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
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Myosin packing Adjoining molecules offset by ~ 14 nm Corresponds to 98 residues of coiled coil
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Associated proteins of Muscle -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
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DystrophinNew Developments!
Dystrophin is part of a large complex of glycoproteins that bridges the inner cytoskeleton (actin filaments) and the extracellular matrix (via a protein called laminin)
Two subcomplexes: dystroglycan and sarcoglycan
Defects in these proteins have now been linked to other forms of muscular dystrophy
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Nick Menhart:BCPS faculty member specializing in dystrophin research
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Dystrophin, actinin,spectrin
Characteristic 3-helix regions
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Spectrin-repeat structure These characteristic 3-helix elements are found in actinin, spectrin, dystrophin
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Spectrin repeatPDB 1AJ3NMR12.8 kDa
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Model for complex
Actin-dystrophin-glycoprotein complex
Dystrophin forms tetramers of antiparallel monomers
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The Dystrophin Complex
Links to disease -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 - , , - all transmembrane - defects linked to limb-girdle MD and autosomal recessive MD
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The Sliding Filament ModelMany contributors!
Hugh Huxley and Jean Hanson Andrew Huxley and Ralph Niedergerke
Albert Szent-Györgyi showed that actin and myosin associate (actomyosin complex)
Sarcomeres decrease length during contraction (see Figure 16.19)
Szent-Gyorgyi also showed that ATP causes the actomyosin complex to dissociate
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Hugh Huxley
Albert Szent-Györgyi
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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
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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
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Mechanism
Fig. 16.20
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Actin-myosin interaction Ribbon- and space-filling representations
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Ivan Rayment
Hazel Holden
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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
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Myosin & kinesin motor domains
Relay helix moves back and forth like a piston
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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
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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
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Ca2+ triggers contraction Release of Ca2+ through voltage- or Ca2+-sensitive channel activates contraction
Pumps induce relaxation
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Dihydropyridine ReceptorIn 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
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Ryanodine ReceptorThe "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!
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Ryanodine Receptor
Courtesy BBRI
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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!
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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
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Thin & thick filaments Changes that happen when Ca2+ binds to troponin C
Fig. 16.24
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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
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2 views of troponin C Ribbon Molecular graphic
Fig. 16.25
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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
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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
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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
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Oxytocin structure P.532