FUNDAMENTALS I: 10:00 – 11:00Scribe: RACHEL TUCKER

TUESDAY, AUGUST 17, 2010Proof: LOUISA WARREN

MILLERMUSCLE PROTEINSPage1 of 3

  1. MUSCLE PROTEINS [S1]
  2. Some slides were dropped from the presentation in the interest of time and convenience. Nothing removed that would choke the balance or remove continuity.
  3. We will answer the question how you translate movement/dynamism on the part of small molecules into macroscopic movement
  4. e.g. flexing of an arm, walking, handling a baseball bat
  5. Those are all movements which depend upon skeletal muscle.
  6. Skeletal muscle works when you want it to work. Consequently, there are controls of movement and energy requirements on movement.
  7. SKELETAL MUSCLE ANATOMY [S2]
  8. A muscle fiber is composed of hundreds of myofibrils which run the length of the fiber
  9. Sarcomere—each myofibril is a series of sarcomeres; the sarcomere is the basic unit of the myofibril
  10. Each sarcomere is capped on each end by a membrane, a transverse tubule, which is an extension of the sarcolemmal membrane.
  11. The surfaces of sarcomeres are covered by a sarcoplasmic reticulum that contains calcium.
  12. This is an important point because all calcium that’s stored up in the periphery of the sarcomere is liberated to set up a contraction.
  13. Calcium is the major factor in initiating contraction.
  14. If you don’t have calcium, you cannot have contractions.
  15. If you have too much calcium then you have catatonic-like contractions
  16. FIGURE: ELECTRON MICROGRAPH OF SKELETAL MUSCLE MYOFIBRIL [S3]
  17. Don’t worry about specific anatomical descriptions (i.e. H-zone, Z-line)
  18. Sarcomere
  19. From one Z-line to another Z-line is one sarcomere
  20. The two sides are mirror images which meet at the H zone:

light region, dark region, intermediate dark region (H-zone) intermediate dark region, dark region, light region

  1. Three regions
  2. Light region: only thin filaments (actin molecules)
  3. Dark region: thick (myosin molecules) and thin filaments
  4. Intermediate dark region: only thick filaments
  5. these regions are described by the boxes in the figure
  1. FIGURE: ACTIN MONOMER [S4]
  2. SKIPPED
  3. FIGURE: HELICAL ARRANGEMENT OF ACTIN MONOMERS IN F-ACTIN [S5]
  4. The actin molecules (represented by blue circles) in the muscle fiber become F-actin (fibrous actin) to form fibers
  5. Two fiber lengths wrap around each other to form a dimer: a coiled coil fiber
  6. Similar to the formation of hemoglobin fibers in sickle cell anemia
  7. Sickle cell anemia is pathological; actin fibers are normal
  8. FIGURE: DIFFERENT WAYS TO ILLUSTRATE AN ACTIN MOLECULE [S6]
  9. Actin fibers are clothed by troponin and tropomyosin which fit into the grooves that are formed on the surfaces of the actin fibers.
  10. No actin monomer is uncovered totally
  11. Important concept because when a muscle contracts, calcium causes these molecules to move away from the actin fiber so that the fiber is susceptible to being traveled upon by the myosin fiber.
  12. THE COMPOSITION AND STRUCTURE OF THICK FILAMENTS [S7]
  13. Myosin quaternary structure: 2 heavy chains and 4 light chains
  14. Myosin essentially exists with two different domains: a fibrous domain (the majority of the heavy chains) and a globular domain (myosin heads, have ATPase activity)
  15. Light chains are homologous to calmodulin and troponin C, tropomyosin, troponin
  16. These are all calcium binding molecules whose activity and structure are based on the presence or absence of calcium in the environment
  17. FIGURE: MYOSIN MOLECULE [S8]
  18. Myosin molecule consists of two heavy chains coiled-coiled around each other:
  19. alpha helices wrapped around each other
  20. coiling of the coils (of the alpha helices) made possible by the heptad repeat of the secondary structure of the alpha helix
  21. Light chains are around the globular heads.
  22. These are regulatory chains which are affected greatly by the presence or absence of calcium
  23. ATPase activity rests in the globular heads of the myosin molecule; this is what the myosin molecule is all about
  24. Something I have not stressed before: In many molecules, there will be a fibrous domain and another domain of the molecule which is globular and formed in the typical fashion of globular proteins. Seen in collagen as well.
  25. REPEATING STRUCTURAL ELEMENTS ARE THE SECRET OF MYOSIN’S COILED COILS [S9]
  26. Molecules are staggered because of the repetitive nature of the primary structure
  27. Heptad repeats are along the primary structure of the myosin coil; every 7 amino acids starts a new set of amino acids in primary structure that are repetitive based on what went before.
  28. The next molecule resides relative to the first molecule by being staggered on the order of 7 repeats.
  29. Actually, there are 14 repeats, but this has been simplified for our purposes.
  30. This type of coiling has been described in terms of secondary structure
  31. Residues 1 and 4 are hydrophobic residues and residues 2, 3, and 6 are ionic in each heptad repeat
  32. FIGURE 16.17 [S10]
  33. The repeat structure places the hydrophobic amino acids 1 and 4 adjacent to each other; gives the ability of the individual chains to interact and wrap around each other.
  34. Take it as a given that the coils wrap around each other to make a coiled coil structure.
  35. Collagen is another wrap around structure.
  36. MORE REPEATS! [S11]
  37. SKIPPED
  38. THE PACKING OF MYOSIN MOLECULES IN A THICK FILAMENT [S12]
  39. This is a stripped down sarcomere only showing the myosin molecules.
  40. The myosin molecules extend from that midpoint of the sarcomere toward the ends of the sarcomere in both directions
  41. The molecules are staggered relative to each other so that as the fiber progresses, the surface of the fiber is essentially covered by the myosin heads; the heads stick out from the fiber at all locations.
  42. FIGURE: ELECTRON MICROGRAPH OF SKELETAL MUSCLE MYOFIBRIL [S13]
  43. We have now only thin filaments in the light area and only thick filaments in the intermediate area. Where thin filaments and thick filaments overlap and give this very dark area.
  44. DISPOSITION OF MUSCLE MOLECULES IN ONE SARCOMERE [S14]
  45. It will all come together right here
  46. Resting sarcomere drawn at the top: Thick filaments are bare in the middle (intermediate region), then region where thin and thick filaments are together (dark region), then region where there are only thin filaments (light region)
  47. Drawing corresponds with electron micrograph of previous slide
  48. Contracting muscle: the myosin heads grab hold of the actin filaments and walk along the actin fibers.
  49. Actin fibers provide the street that the myosin heads walk along
  50. Myosin heads progress down and pull the actin filaments together
  51. Sarcomere length decreases; each end contracts
  52. Myosin fibers don’t move themselves, they just pull the actin fibers along.
  53. Treadmill: myosin fibers don’t move as they walk, but the actin fibers (treadmill) do.
  54. HOW DOES THE SYSTEM WORK? [S15]
  55. SKIPPED
  56. THE MECHANISM OF SKELETAL MUSCLES CONTRACTION [S16]
  57. Relaxed fiber
  58. The myosin head is not attached to the actin filament
  59. The myosin fiber has ADP and phosphate attached to its head. ATP has been hydrolyzed, which causes the myosin head to go into a low energy/resting state.
  60. Nerve impulse
  61. Calcium comes and stimulates a release of ADP and phosphate molecules.
  62. That releases the energy given to the myosin head by ATP hydrolysis and the actual myosin head will now attach to the actin fiber and undergo a power stroke.
  63. The power stroke: the head will move to the left as you look at the diagram, and pull the actin filament to the left
  64. Myosin head remains attached to the actin filament after the power stroke.
  65. To release the myosin head from the actin filament
  66. Must have molecule of ATP come in to cause the myosin head to relax, give up its binding site on the myosin filament and head back to the relaxed state.
  67. Once ATP is hydrolyzed, the myosin head goes back to the fully relaxed state and is detached from the actin
  68. This process takes place at the rate of 5 strokes/second
  69. Rigor mortis tipped off scientists about how muscle contraction works
  70. When an individual dies, there is an inability to move the muscle.
  71. Reason: myosin heads become attached to the actin filament and the muscle is stuck in this position. There’s no ATP coming in to cause a resetting of the myosin-actin interaction. Must reset that in order to get relaxation, and must be alive to make ATP.
  72. CALCIUM IS THE TRIGGER SIGNAL FOR MUSCLE CONTRACTION [S17]
  73. Calcium sets off the entire process. Without calcium, you can have no muscle contraction
  74. Lumen of sarcoplasmic reticulum contains a load of calcium in the muscle tissue for use in contraction.
  75. Nerve stimulation
  76. Passageway for calcium to leave the sarcoplasmic reticulum and go to the muscle fibers is open.
  77. Muscle becomes loaded with calcium which pours down to the muscle fibers
  78. When the contraction has stopped and sufficient calcium has been delivered, there’s a calcium pump that acts by virtue of the energy given by ATP to take calcium back out of the muscle to the sarcoplasmic reticulum.
  79. Why is calcium so necessary? Calcium uncovers sites on actin filaments where myosin head grabs hold of the filament
  80. DRAWING OF THICK AND THIN FILAMENTS OF SKELETAL MUSCLE… [S18]
  81. Tropomyosin, troponin, troponin C, troponin I lie all over the actin filaments
  82. Black dots in diagram are the myosin binding sites
  83. Calcium causes all of these molecules to become dissociated from the binding site and allow the myosin head to be in contact with the actin filament
  84. Imbalance of calcium metabolism catatonic state: either constantly shaking (too much) or constantly flaccid (too little)
  85. SMOOTH MUSCLE CONTRACTION [S19]
  86. Different system works in smooth muscle.
  87. Smooth muscle is generally associated with autonomic function (GI tract, uterine contractions, contractions/relaxations of blood vessels)
  88. Calcium activates myosin light chain kinase (MLCK), which phosphorylates the myosin head and triggers the myosin head to attach to the actin filament.
  89. Calcium functions here, but in a much different way (enzyme activation): no troponin hanging over actin filaments.
  90. Hormones regulate contraction as well
  91. Epinephrine: relaxes muscles by inhibiting kinase, which in turn cannot activate the myosin head. With the myosin head inactive, smooth muscle relaxes.
  92. SMOOTH MUSCLE EFFECTORS [S20]
  93. Epinephrine is a type of drug which is used to cause the smooth muscle cell to relax (asthma)
  94. Albuterol is a more selective muscle relaxer and does not have such a large effect on the heart (prevent premature labor)
  95. Oxytocin is a very famous hormone (small peptide, 9 amino acids with 1 disulfide bond) which stimulates contraction (induce labor)

[End 33:56 mins]