Myosin Motors and Muscle Contraction

Myosin: Defined as the prototype of ATP-driven molecular motors.
Muscle Fibers: These are the large single cells that compose muscles. * They are multinucleated. * They form through the fusion of individual cells called myoblasts.
Myofibrils: Inside each muscle fiber are many myofibrils, which are cylindrical bundles of actin and myosin filaments.
Sarcomeres: These are the repeating contractile units within myofibrils. * Bounded by structures known as Z discs. * The ordered arrangement of actin and myosin filaments within the sarcomere is responsible for the striated (striped) appearance of skeletal muscle and its contractile power.
Filament Organization: * Actin Filaments (Thin Filaments): Formally anchored to the Z discs at either end of the sarcomere. * Myosin Filaments (Thick Filaments): These interdigitate with the actin filaments and are centered at the M line of the sarcomere.

The Mechanism: Muscle contraction results from actin and myosin filaments sliding past one another; it is not caused by the shortening of the filaments themselves.
Sarcomere Shortening: During contraction, the actin filaments slide inward toward the middle of the sarcomere (toward the M line).
Filament Length: There is no change in the actual length of the filaments during contraction; only the relative movement between them changes.
Polarity: The orientation of both actin and myosin filaments reverses at the M line, ensuring that the relative polarity is identical on both sides of the sarcomere, allowing for symmetrical contraction.

Myosin II (Conventional Myosin): The specific type of myosin found in muscle cells.
Molecular Composition: Consists of two heavy chains and two pairs of light chains. * Heavy Chains: Each heavy chain contains a globular head region and a long $\alpha$ -helical tail. * Heads: The globular heads bind both actin and ATP to generate movement. * Tails: The $\alpha$ -helical tails coil around each other to form dimers. * Light Chains: There are two pairs, referred to as the essential light chains and the regulatory light chains, which modulate the activity of the myosin head.
Thick Filament Assembly: Thick filaments are formed by the association of several hundred myosin II molecules arranged in a staggered array.
Cross-Bridges: The globular heads of myosin bind to actin to form cross-bridges between the thick and thin filaments, providing the force needed for sliding.

Titin: A giant elastic protein that extends from the Z disc to the M line. * Acts as a molecular spring to keep myosin filaments centered within the sarcomere. * Helps restore the muscle to its resting length after contraction.
Nebulin: A protein that aligns actin filaments to ensure they maintain a uniform length.
Tropomyosin: A protein that runs lengthwise along actin filaments; it regulates the access of myosin heads to their binding sites on actin.

The interaction between actin and myosin is powered by ATP hydrolysis. Each cycle consumes one molecule of ATP and produces approximately $10\,nm$ of filament displacement.
Step 1: Dissociation: The binding of ATP to the myosin head causes the myosin to release its grip on the actin filament.
Step 2: Cocking: ATP hydrolysis ( $ATP \rightarrow ADP + P_i$ ) induces a conformational change that alters the position of the myosin head (the "cocked" position), storing energy.
Step 3: Binding: The myosin head binds to a new position on the actin filament.
Step 4: Power Stroke: The release of inorganic phosphate ( $P_i$ ) triggers the power stroke. The myosin head returns to its original conformation, pulling the actin filament toward the center of the sarcomere.
Step 5: ADP Release: The release of ADP leaves the myosin head attached to the actin in its original conformation, ready for a new molecule of ATP to start the cycle again.

The Troponin Complex: Associated with tropomyosin on the actin filament, consisting of three subunits: * TnI (Troponin I): An inhibitory subunit that prevents the interaction between actin and myosin. * TnT (Troponin T): Anchors the troponin complex to tropomyosin. * TnC (Troponin C): Binds to calcium ions.
Activation Mechanism: * In the absence of $Ca^{2+}$ (resting state), the tropomyosin–troponin complex blocks the myosin-binding sites on actin. * When an action potential triggers the release of $Ca^{2+}$ from the sarcoplasmic reticulum (SR), the $Ca^{2+}$ binds to TnC. * This binding causes a shift in the tropomyosin–troponin complex, uncovering the myosin-binding sites and allowing the cross-bridge cycle to proceed.
Relaxation: Contraction stops when $Ca^{2+}$ is pumped back into the sarcoplasmic reticulum, allowing tropomyosin to re-block the binding sites.

Myosin II also functions in nonmuscle cells to drive localized contractions via bipolar myosin II filaments that slide actin filaments in opposite directions.
Stress Fibers: Large bundles of actin and myosin that provide tension and anchor cells to focal adhesions.
Adhesion Belts: Networks of actin and myosin that link the junctions between epithelial cells.
Cytokinesis and the Contractile Ring: Following the completion of mitosis (nuclear division), a contractile ring composed of actin filaments and myosin II forms to divide the cytoplasm, splitting the cell into two.

In nonmuscle cells, contraction is regulated primarily by the phosphorylation of the myosin regulatory light chain.
Regulation Pathway: * An increase in cytosolic $Ca^{2+}$ leads to $Ca^{2+}$ binding to a protein called calmodulin. * The $Ca^{2+}$ -calmodulin complex binds to and activates an enzyme called Myosin Light-Chain Kinase (MLCK). * Active MLCK phosphorylates the regulatory light chain of myosin II. * This phosphorylation converts myosin from an inactive state to an active, filament-forming state, enabling contraction in response to signaling cues.

Unconventional myosins differ from Myosin II because they do not form filaments and are not involved in muscle contraction.
They function as cargo transport motors that move along actin filaments toward the plus ( $+$ ) end.
Myosin I: * A single-headed motor with a comparatively short tail. * Uses ATP hydrolysis to move cargoes, such as membrane vesicles, along actin filaments. * Acts as a link between actin filaments and the plasma membrane, assisting in membrane remodeling and endocytosis.
Myosin V: * A two-headed motor that is processive (remains attached for long distances). * Transports larger cargoes including organelles, vesicles, and intermediate filaments toward the plus ends of actin tracks. * Essential for intracellular organization and the distribution of cargo within the cell.