Myosin

Myosins are a superfamily of motor proteins that convert the chemical energy of ATP into force and movement along actin filaments, powering muscle contraction and many kinds of transport inside cells. Every heartbeat, step, and breath depends on myosin heads pulling on actin billions of times per second across the body's muscles.

Humans have around 40 myosin genes, grouped into classes by the structure of their tails. Class II, the "conventional" myosin of muscle, was the first discovered; the others, collectively called unconventional myosins, carry cargo, shape cells, and help build structures such as the hair cells of the inner ear.

A typical myosin has three regions:

• Head (motor domain): Binds actin and hydrolyzes ATP. It is the engine of the molecule.
• Neck (lever arm): A long α-helix stabilized by light chains. Small changes in the head are amplified into a large swing of the lever arm.
• Tail: Varies between classes and decides what the myosin does, whether forming filaments or binding membranes and cargo.

Myosin II, the muscle form, is a hexamer of two heavy chains and four light chains (two essential and two regulatory). Its two heads sit at one end, and its long coiled-coil tails pack together with hundreds of others to form the thick filaments of muscle.

Myosin produces movement through a repeating cycle of binding, pulling, and releasing:

1. Detachment: ATP binds the myosin head, which then lets go of actin.
2. Recovery stroke: The head hydrolyzes ATP into ADP and phosphate and swings into a "cocked" position.
3. Attachment: The cocked head binds weakly to a new site on actin.
4. Power stroke: Release of phosphate triggers the lever arm to swing, pulling the actin filament several nanometers.
5. Rigor state: ADP is released, leaving the head tightly bound to actin until a new ATP arrives.

Without ATP, heads cannot detach, so muscles lock in place. This is the molecular basis of rigor mortis after death, when ATP production stops.

Most myosins move toward the "plus" (barbed) end of actin filaments. Myosin VI is a notable exception that walks toward the minus end, allowing it to carry cargo in the opposite direction.

In skeletal and cardiac muscle, actin and myosin are arranged in repeating units called sarcomeres. According to the sliding filament theory, proposed in 1954 by two research teams (Andrew Huxley and Rolf Niedergerke, and Hugh Huxley and Jean Hanson), muscles shorten because thin actin filaments slide past thick myosin filaments, without the filaments themselves changing length.

Contraction is switched on by calcium:

• In skeletal and cardiac muscle, the protein tropomyosin covers myosin-binding sites on actin. When a nerve signal triggers calcium release, calcium binds troponin, which shifts tropomyosin aside and lets myosin heads attach.
• In smooth muscle, calcium works through calmodulin to activate myosin light chain kinase, which phosphorylates myosin's regulatory light chain and turns the motor on.

Beyond muscle, myosins carry out many jobs in the cytoskeleton:

• Myosin V is a two-headed motor that "walks" hand over hand along actin in steps of about 36 nanometers, carrying vesicles, pigment granules, and organelles.
• Non-muscle myosin II forms the contractile ring that pinches a cell in two during cell division, and powers the crawling movement of migrating cells.
• Myosin VII and XV help build and maintain the stereocilia of inner-ear hair cells; mutations in their genes cause inherited deafness.

Mutations in MYH7, which encodes the main heavy chain of the heart's ventricles, are among the most common causes of hypertrophic cardiomyopathy, an inherited thickening of the heart muscle. Many disease mutations make the motor too active. This led to the development of cardiac myosin inhibitors: mavacamten, approved by the U.S. FDA in 2022 for obstructive hypertrophic cardiomyopathy, reduces the number of myosin heads available for contraction.

Myosin is one of the clearest examples of how proteins turn chemical energy into mechanical work, a central theme of biophysics and bioenergetics and cellular metabolism.