Biochemistry Exam Iv - Muscle Contraction

Front 1

Minimum requirements for movement: Myosin + ATP + actin

Movement is the product of this reaction

Need to have both substrates saturating (myosin and ATP)

Back 1

The cofactor, actin, behaves as a substrate.

Both ATP and actin follow Michaelis-Menten Kinetics

Front 2

Actin = Myosin + ATP <--> Actin < Myosin + ADP + Pi

Back 2

“Movement” is one product of this reaction.

Front 3

Use of a lever magnifies the conformational change and gives us movement power

Product of this enzymatic reaction is force

Back 3

What makes the conformational changes of myosin differ from other “non - motor ”enzymes?

Front 4

1. Phosphorylation of myosin is required for smooth muscle contraction.

2. Phosphorylation of myosin enhances the contraction to a small extent in cardiac and skeletal muscle.

3. Myosin light chain kinase is activated by calcium-calmodulin.

4. Myosin phosphatase is also regulated.

Back 4

Muscle contraction is tightly regulated.

The regulation is tissue specific

Front 5

Myosin regulated/phosphorylated tissue

Acts as kinase.

Back 5

Smooth muscle contraction

Some cardiac and skeletal muscle.

Phosphatase is also necessary and regulated

Front 6

________ is only present in striated muscle (good test question)

Back 6

Troponin

Front 7

1. Each tropomyosin lies along 7 actin protomers.

2. Tropomyosin position controls activity.

3. Both troponin and myosin can control the position of tropomyosin on actin.

4. Troponin is the major controller of tropomyosin position.

5. Troponin stabilizes the inactive position at low calcium concentrations

Back 7

Troponin-tropomyosin in striated muscle.

How actin regulates contraction

Front 8

What is the role of Ca2+ in striated (skeletal and cardiac) muscle contraction?

Back 8

Complexity allows "allosteric" control that allows fine-tuned control of muscles

Troponin holds tropomyosin and actin in the unfavorable conformation till Ca2+ releases it

Front 9

Calcium causes troponin to let go of actin, allowing tropomyosin-troponin to move into a more active state.

What happens next?

Back 9

The troponin-actin interaction is lost when calcium binds. Tropomyosin can then move to a more active position.

Front 10

Force producing crossbridges (FPB) further activate the system irrespective of calcium.

But such crossbridges are likely only during calcium activation

Back 10

ATP binding allows fully active FPB, Ca only makes FPB partially active

Front 11

Inhibited + FPB -> Fully active

Partially active (+Ca2+) + FPB -> fully active

Back 11

Remember that Force producing crossbridges activate the system regardless of calcium.

However, most times will need calcium to prepare the crossbridging.

Front 12

If calcium is low, tropomyosin in _______ state

Back 12

inactive

Front 13

Calcium binds to ________

Back 13

Troponin C (Tpn C)

Front 14

Tropomyosin released to ___________ distribution…more active state.

Back 14

equilibrium

Front 15

If ATPase rate increases, what event will happen?

Back 15

contraction occurs.

Front 16

Myosin-ADP binding fully moves __________ to to active state.

Back 16

tropomyosin

Front 17

Nemaline Myopathy

Back 17

skeletal muscle disorders

Front 18

Familial Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Restrictive Cardiomyopathy

Back 18

cardiac muscle disorders

Front 19

- Myopathies (acute quadriplegic)
- Cardiomyopathies (familial hypertrophic)
- Hearing Loss (i.e. Usher syndrome)
- Blindness (i.e. Usher syndrome)
- Developmental irregularities
- Pigment Loss (Griscelli syndrome)
- Hematologic irregularities (thrombocytopenia; May-Hegglin anomaly)

Back 19

Myosin Motor Disorders:

not always what you expect…

Front 20

Any eukaryotic transport process is a target for disorders of molecular motors

Back 20

As the volume grows the surface area cannot keep up.

Front 21

- Myosin
- Actin or proteins that control polymerization
- Regulatory proteins that control the activity of Myosin-Actin

Back 21

Muscle Disorders May result From Defects in…

Front 22

Toxins like cytochalasin _______ polymerization.

Back 22

inhibit

Actin polymerization highly regulated.

Front 23

Phalloidin _________ depolymerization.

Back 23

prevents

Actin polymerization highly regulated.

Front 24

Contraction requires myosin, actin and accessory proteins.

Defects in any of these proteins = trouble

Disorders resulting from myosin defects depend on the isozyme affected.

Regulation of striated muscle is cooperative and requires troponin and tropomyosin.

Back 24

Calcium gives partial activation.

Full activation requires “activating” crossbridge binding.

Alteration of the distribution among inactive, intermediate and active states may produce cardiomyopathies.

Front 25

The functional unit of a striated muscle is the sarcomere.

Shortening occurs when the thick (myosin) filaments slide past the thin (actin) filaments.

Shortening requires ATP hydrolysis and an activating signal.

Myosin binding to actin is essential for rapid ATP hydrolysis.

Force is produced when the active site of myosin (S1) undergoes a large conformational change as ADP and Pi are released from the cleaved ATP

Back 25

Summary of movement

Front 26

When ______ has bound ATP or ADP+Pi, the binding is weak and is very rapid.

This type of binding can occur in relaxed muscle.

Back 26

myosin

Front 27

When Pi is released, myosin binds to actin differently. The binding is much stronger and the rate of detachment from actin is much slower.

This change in binding produces force.

Back 27

Actin is necessary both the rapid release of products and for movement.

Front 28

The regulatory proteins of striated muscle are tropomyosin and troponin.

One troponin and one tropomyosin are bound to each ___ actin monomers.

Back 28

7

Front 29

Troponin is not bound to actin in the presence of calcium and tropomyosin is free to move to its neutral position.

Back 29

Here the ATPase rate is about 25% of the maximum value.

Front 30

In the absence of calcium, troponin locks tropomyosin into the inactive position…very low ATPase activity.

Back 30

No contraction can occur in this state.

Front 31

High levels of myosin with bound ADP can trap the tropomyosin in the fully active state.

Back 31

Not dependent on calcium

Front 32

Some TnT mutations give more than 25% of the maximum rate in Calcium

Back 32

Mutations of troponin change the normal distribution of states.

Lead to cardiomyopathies.

Front 33

Some mutations of TnI give less than 25% of the maximum rate in Calcium.

Back 33

Mutations of troponin change the normal distribution of states.

Lead to cardiomyopathies.

Front 34

Thickening interferes with normal functioning of the heart by: - narrowing the outflow of the ventricle - reducing the ability of the heart to relax and fill with blood during the relaxation phase.

Reduces the ability of the valves of the heart to function properly.

Back 34

Hypertrophic Cardiomyopathy

Any situation that increases the contraction or rate of contraction of the heart muscle can worsen these symptoms.

Front 35

Prevalence of 1:500 individuals. Most common cause of sudden death in the young.

Cause of left ventricular hypertrophy is unexplained.

Incompletely penetrant; different family members have different outcomes.

Familial Cardiomyopathies result from mutations in any of the major contractile proteins.

Back 35

Hypertrophic Cardiomyopathy

Front 36

Some mutations reduce ATPase activity and favor formation of the less active states.

Some mutations increase ATPase activity and favor formation of the more active states.

Back 36

These events lead to heart failure.

Front 37

Regulation of _______ muscle is cooperative and requires troponin and tropomyosin.

Calcium gives partial activation.

Full activation requires “activating” crossbridge binding.

Alteration of the distribution among inactive, intermediate and active states may produce cardiomyopathies.

Back 37

striated

Front 38

Identify X

Back 38

Front 39

Identify Y

Back 39

Front 40

Back 40

Front 41

Back 41

Front 42

Back 42

Dependence of actin ATPase on actin concentration