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Muscle Contraction

Muscle Contraction. Andy Howard Introductory Biochemistry 2 December 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. Skeletal muscle physiology

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Muscle Contraction

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  1. Muscle Contraction Andy HowardIntroductory Biochemistry 2 December 2008 Biochemistry: Muscles

  2. 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

  3. 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 What we’ll discuss Biochemistry: Muscles

  4. 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 Prof. Thomas C. Irving Biochemistry: Muscles

  5. Skeletal Muscle Cell • T-tubules enable the sarcolemmal membrane to contact the ends of the myofibril Biochemistry: Muscles

  6. 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

  7. 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

  8. 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

  9. Myo- fibrils • Hexagonal arrays shown(fig. 16.12) Biochemistry: Muscles

  10. Actin monomer • One domain on each side(16.13) Biochemistry: Muscles

  11. Actin helices • Pitch = 72nm • Repeat = 36 nm • Fig.16.14 Biochemistry: Muscles

  12. 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

  13. 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

  14. Myosin • Cartoon • EM • S1 myosin head structure Biochemistry: Muscles

  15. 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

  16. Axial view (fig. 16.17) Myosin tail: 2-stranded -helical coiled coil Biochemistry: Muscles

  17. 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

  18. Myosin packing • Adjoining molecules offset by ~ 14 nm • Corresponds to 98 residues of coiled coil Biochemistry: Muscles

  19. 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 Biochemistry: Muscles

  20. Dystrophin New 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 Nick Menhart:BCPS faculty member specializing in dystrophin research Biochemistry: Muscles

  21. Dystrophin, actinin,spectrin • Characteristic 3-helix regions Biochemistry: Muscles

  22. Spectrin-repeat structure • These characteristic 3-helix elements are found in actinin, spectrin, dystrophin Spectrin repeatPDB 1AJ3NMR12.8 kDa Biochemistry: Muscles

  23. Model for complex • Actin-dystrophin-glycoprotein complex • Dystrophin forms tetramers of antiparallel monomers Biochemistry: Muscles

  24. 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 Biochemistry: Muscles

  25. Hugh Huxley The Sliding Filament Model Many 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 Albert Szent-Györgyi Biochemistry: Muscles

  26. 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

  27. 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

  28. Mechanism • Fig. 16.20 Biochemistry: Muscles

  29. Actin-myosin interaction • Ribbon- and space-filling representations Ivan Rayment Hazel Holden Biochemistry: Muscles

  30. 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

  31. Myosin & kinesin motor domains • Relay helix moves back and forth like a piston Biochemistry: Muscles

  32. 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

  33. 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

  34. Ca2+ triggers contraction • Release of Ca2+ through voltage- or Ca2+-sensitive channel activates contraction • Pumps induce relaxation Biochemistry: Muscles

  35. 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

  36. 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

  37. Ryanodine Receptor • Courtesy BBRI Biochemistry: Muscles

  38. 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

  39. 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

  40. Thin & thick filaments • Changes that happen when Ca2+ binds to troponin C • Fig. 16.24 Biochemistry: Muscles

  41. 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

  42. 2 views of troponin C • Ribbon • Molecular graphic • Fig. 16.25 Biochemistry: Muscles

  43. 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

  44. 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

  45. 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

  46. Oxytocin structure • P.532 Biochemistry: Muscles

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