Myosin

Myosins are a family of motor proteins—often forming protein complexes—that are best known for driving muscle contraction and a variety of other movement processes in eukaryotic cells. They depend on ATP and are responsible for movement along actin filaments. The first myosin, now called M2, was identified in 1864 by Wilhelm Kühne. He extracted a viscous protein from skeletal muscle, which he believed maintained muscle tension, and named it myosin. Since then, the term has been expanded to include a group of similar ATPases found in both striated and smooth muscle tissues. In 1973, enzymes with myosin-like functions were discovered in *Acanthamoeba castellanii*, leading to the identification of many divergent myosin genes across the eukaryotic kingdom. Although myosin was once thought to exist only in muscle cells (hence the name, from *myo-* meaning muscle), it is actually a large superfamily of genes. Their protein products share core traits: they bind actin, hydrolyze ATP (acting as ATPases), and transduce force. Nearly all eukaryotic cells contain myosin isoforms. Some isoforms have specialized roles in certain cell types, such as muscle, while others are found universally. The structure and function of myosin are highly conserved across species—so much so that rabbit muscle myosin II can bind to actin from an amoeba. **Structure and Functions**

Most myosin molecules have three domains: a head, a neck, and a tail. The head domain binds to filamentous actin and uses ATP hydrolysis to generate force and "walk" toward the barbed (+) end of the filament (except myosin VI, which moves toward the pointed (-) end). The neck domain acts as a linker and a lever arm, transmitting force from the catalytic motor domain. It can also bind myosin light chains—separate proteins that form part of the macromolecular complex and usually have regulatory roles. The tail domain typically mediates interactions with cargo molecules or other myosin subunits, and in some cases, it helps regulate motor activity. **Power Stroke**

In skeletal muscle, multiple myosin II molecules generate force through a power stroke mechanism, fueled by energy from ATP hydrolysis. The power stroke occurs when phosphate is released from the myosin molecule after ATP hydrolysis, while myosin is tightly bound to actin. This release causes a conformational change that pulls against the actin. The release of ADP leads to the so-called rigor state of myosin. Binding a new ATP molecule releases myosin from actin. ATP hydrolysis within myosin then causes it to bind actin again, repeating the cycle. The combined effect of many power strokes causes muscle contraction. **Nomenclature, Evolution, and the Family Tree**

The wide variety of myosin genes across eukaryotic phyla were named under different schemes as they were discovered, making nomenclature confusing when comparing myosin functions within and between organisms. Skeletal muscle myosin—the most conspicuous due to its abundance in muscle fibers—was the first discovered. It forms part of the sarcomere and creates macromolecular filaments made of multiple myosin subunits. Similar filament-forming myosins were later found in cardiac muscle, smooth muscle, and nonmuscle cells. Starting in the 1970s, researchers discovered new myosin genes in simple eukaryotes that encoded monomeric proteins, called Class I myosins. These were termed "unconventional myosins" and have been found in many tissues beyond muscle. They are grouped into classes based on phylogenetic relationships derived from comparing amino acid sequences of their head domains, with each class assigned a Roman numeral. Unconventional myosins also have divergent tail domains, suggesting unique functions. The diverse array of myosins likely evolved from an ancestral precursor. Analysis of myosin amino acid sequences shows great variability among tail domains but strong conservation of head domain sequences. This likely allows myosins to interact, via their tails, with many different cargoes, while the shared goal—moving along actin filaments—requires the same motor machinery. For example, the human genome contains over 40 different myosin genes. Differences in shape also determine how fast myosins move along actin filaments. ATP hydrolysis and phosphate release cause the power stroke, dragging the lever arm (neck region) forward. Since the power stroke always moves the lever arm by the same angle, the lever arm’s length determines how far the cargo moves relative to the actin filament. A longer lever arm means a greater distance per step, just as a person with longer legs takes larger strides. The velocity of a myosin motor depends on how quickly it completes a full kinetic cycle, from ATP binding to ADP release. **Myosin Classes**

**Myosin I** is a ubiquitous cellular protein that functions as a monomer and is involved in vesicle transport. It has a step size of 10 nm and is thought to be responsible for the adaptation response of stereocilia in the inner ear.