Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
5.3 Protein Interactions Modulated by Chemical Energy: Actin, Myosin, and Molecular Motors
This chapter explains how chemical energy (usually from ATP) drives protein-protein interactions to generate force and movement in living systems, focusing on the actin-myosin system in skeletal muscle as a model for molecular motors.
Overview of Molecular Motors and Protein Interactions
• Organismal, cellular, and intracellular movement is made possible by protein-based molecular motors—large protein complexes that convert chemical energy (mostly from ATP) into directed movement.
• Motor proteins operate through cyclic conformational changes and highly organized spatial and temporal interactions among binding sites (ionic, hydrogen-bonding, hydrophobic interactions).
• Motor proteins are involved in a wide range of biological movements: muscle contraction, migration of organelles along microtubules, bacterial and eukaryotic flagellar motion, and movement of proteins along DNA.
• Skeletal muscle contraction is the classic and most studied paradigm for how proteins translate chemical energy into motion.
Major Proteins of Muscle: Myosin and Actin
• Myosin (about 520,000 Da) has six subunits: two long heavy chains (each about 220,000 Da) and four small light chains (each about 20,000 Da).
• The heavy chains form an extended α-helical coiled coil "tail" (C-termini) and globular "head" domains (N-termini), where ATP hydrolysis and actin binding occur; light chains associate with the head domains.
• Myosin aggregates to form thick filaments—bipolar rodlike structures with tails in the core and globular heads projecting outward.
• Actin exists as G-actin (globular monomer, 42,000 Da) and F-actin (filamentous polymer). F-actin forms thin filaments by polymerization, with each monomer binding ATP and hydrolyzing it to ADP during filament assembly.
• Each actin monomer in the thin filament can bind tightly and specifically to one myosin head.
Muscle Ultrastructure and Filament Organization
• Skeletal muscle consists of parallel bundles of large, multinucleated muscle fibers, each containing about 1,000 myofibrils.
• Myofibrils contain regular arrays of thick (myosin) and thin (actin) filaments, creating alternating high- and low-density bands (A bands and I bands) seen by electron microscopy.
• The contractile unit is the sarcomere—bundles of thick and thin filaments interleaved, anchored by Z disks (for thin filaments) and bisected by M lines (in thick filaments).
• Muscle contraction results from thick and thin filaments sliding past each other, shortening each sarcomere and bringing Z disks closer together.
Molecular Mechanism of Muscle Contraction
• Actin-myosin interaction is based on reversible, weak bonds—myosin head binds actin tightly when ATP is absent.
• The ATP hydrolysis cycle in myosin drives conformational changes:
• (1) ATP binds myosin, causing myosin to release actin.
• (2) ATP is hydrolyzed, shifting myosin to a high-energy state and moving the head relative to actin.
• (3) Myosin binds a new actin site closer to the Z disk, releases phosphate, and strengthens the interaction.
• (4) The "power stroke" returns myosin head to its original conformation, moving thick filament relative to thin filament, and ADP is released—completing the cycle.
• Each cycle generates 3–4 piconewtons of force and moves the filament 5–10 nm. Many myosin heads work together to create macroscopic muscle contraction.
• At any instant, only a small percentage of myosin heads are attached, preventing slippage during the cycle.
Regulation of Contraction: Tropomyosin and Troponin
• Tropomyosin (a two-stranded coiled coil) and troponin regulate contraction by blocking or exposing myosin-binding sites on F-actin.
• In relaxed muscle, tropomyosin blocks the binding sites. Upon nerve stimulation, Ca2+ ions are released from the sarcoplasmic reticulum and bind troponin C, causing a conformational change that shifts tropomyosin, exposing binding sites and allowing contraction.
• Troponin consists of three subunits: I (inhibitory, blocks myosin binding), C (binds Ca2+), and T (links troponin to tropomyosin).
Functional Importance: Reversibility and Enzyme Activity
• Actin-myosin binding is reversible and essential for repeated muscle cycles; irreversible binding results in rigor mortis.
• Myosin is both an actin-binding protein and an ATPase enzyme, coupling chemical catalysis to mechanical movement.
In a Nutshell
• Muscle contraction and many other cellular movements are powered by molecular motors (myosin, actin) using the chemical energy from ATP to drive cyclic, coordinated protein-protein interactions.
• The structural organization and regulation of thick and thin filaments ensure efficient, controlled force generation in muscle and exemplify fundamental principles of molecular motors and energy conversion in biology.