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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

Muscle Contraction

Andy HowardIntroductory Biochemistry

2 December 2008

Biochemistry: Muscles

chemistry of muscle contraction
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

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

What we’ll discuss

Biochemistry: Muscles

essential question
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

skeletal muscle cell
Skeletal Muscle Cell
  • T-tubules enable the sarcolemmal membrane to contact the ends of the myofibril

Biochemistry: Muscles

what are t tubules and sr for
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

t tubules and sr continued
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

molecular mechanism of contraction
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

myo fibrils
Myo- fibrils
  • Hexagonal arrays shown(fig. 16.12)

Biochemistry: Muscles

actin monomer
Actin monomer
  • One domain on each side(16.13)

Biochemistry: Muscles

actin helices
Actin helices
  • Pitch = 72nm
  • Repeat = 36 nm
  • Fig.16.14

Biochemistry: Muscles

thin filament
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

composition structure of thick filaments
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

myosin
Myosin
  • Cartoon
  • EM
  • S1 myosin head structure

Biochemistry: Muscles

repeating structural elements are the secret of myosin s coiled coils
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

axial view fig 16 17
Axial view (fig. 16.17)

Myosin tail: 2-stranded -helical coiled coil

Biochemistry: Muscles

more myosin repeats
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

myosin packing
Myosin packing
  • Adjoining molecules offset by ~ 14 nm
  • Corresponds to 98 residues of coiled coil

Biochemistry: Muscles

associated proteins of muscle
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

dystrophin
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

dystrophin actinin spectrin
Dystrophin, actinin,spectrin
  • Characteristic 3-helix regions

Biochemistry: Muscles

spectrin repeat structure
Spectrin-repeat structure
  • These characteristic 3-helix elements are found in actinin, spectrin, dystrophin

Spectrin repeatPDB 1AJ3NMR12.8 kDa

Biochemistry: Muscles

model for complex
Model for complex
  • Actin-dystrophin-glycoprotein complex
  • Dystrophin forms tetramers of antiparallel monomers

Biochemistry: Muscles

the dystrophin complex
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

the sliding filament model

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

sliding filaments
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

the contraction cycle
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

mechanism
Mechanism
  • Fig. 16.20

Biochemistry: Muscles

actin myosin interaction
Actin-myosin interaction
  • Ribbon- and space-filling representations

Ivan Rayment

Hazel Holden

Biochemistry: Muscles

similarities in motor proteins
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

myosin kinesin motor domains
Myosin & kinesin motor domains
  • Relay helix moves back and forth like a piston

Biochemistry: Muscles

intramolecular communication conformational changes
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

muscle contraction is regulated by ca 2
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

ca 2 triggers contraction
Ca2+ triggers contraction
  • Release of Ca2+ through voltage- or Ca2+-sensitive channel activates contraction
  • Pumps induce relaxation

Biochemistry: Muscles

dihydropyridine receptor
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

ryanodine receptor
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

ryanodine receptor37
Ryanodine Receptor
  • Courtesy BBRI

Biochemistry: Muscles

muscle contraction is regulated by ca 238
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

ca 2 turns on contraction
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

thin thick filaments
Thin & thick filaments
  • Changes that happen when Ca2+ binds to troponin C
  • Fig. 16.24

Biochemistry: Muscles

binding of ca 2 to troponin c
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

2 views of troponin c
2 views of troponin C
  • Ribbon
  • Molecular graphic
  • Fig. 16.25

Biochemistry: Muscles

smooth muscle contraction
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

effect of hormones on smooth muscle
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

smooth muscle effectors
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

oxytocin structure
Oxytocin structure
  • P.532

Biochemistry: Muscles