Actin and myosin are the two proteins most responsible for generating mechanical force inside your cells. Together they power muscle contraction, but their partnership extends far beyond movement: they split dividing cells in two, shuttle cargo along internal highways, help you hear, and even work inside the cell nucleus to organize DNA. The human genome encodes nearly 40 myosin genes spread across at least 12 distinct classes, while actin ranks among the most abundant proteins in virtually every cell type.1PubMed. Myosins: tails (and heads) of functional diversity Understanding how they are built, how they interact, and what goes wrong when they malfunction sheds light on everything from heart disease to bacterial infection.
What Actin Looks Like and How It Assembles
Actin exists in two states. In its soluble form it floats as a single globular unit, and in this state it has an ATP molecule tucked into a binding cleft. When conditions are right, these single units spontaneously link together end to end, building long, thin filaments.2PubMed Central. Actin and Actin-Binding Proteins The transition from solitary globule to polymer triggers a conformational flattening of each subunit, which in turn speeds up the hydrolysis of that bound ATP.3PubMed Central. Mechanism of actin polymerization revealed by cryo-EM structures of actin filaments with three different bound nucleotides ATP hydrolysis does not drive assembly itself, but it serves as a kind of built-in timer. Freshly added subunits still hold ATP or its first breakdown product, forming a stabilizing cap at the growing end. As the cap ages and the final phosphate group leaves, the older interior of the filament becomes less stable, priming it for disassembly.4PubMed. Actin polymerization and ATP hydrolysis
This chemistry gives actin filaments a built-in polarity. One end, called the barbed end, grows and shrinks quickly. The other, the pointed end, is far more sluggish because its terminal subunit tilts inward and forms extra contacts that resist both the addition and the loss of new units.5PubMed Central. Structural basis for the slow dynamics of the actin filament pointed end The result is treadmilling: fresh subunits arrive at the barbed end while old ones fall off the pointed end, keeping the filament roughly the same length even though it is constantly turning over. Different actin networks inside the same cell can treadmill at different rates, and recent work suggests that the total pool of available monomers acts as a global budget, limiting how large any one network can grow.6Nature Reviews Molecular Cell Biology. Global treadmilling coordinates actin turnover and controls the size of actin networks
Getting Filaments Started and Taking Them Apart
Left to its own devices, actin is slow to start a new filament because the first few subunits make a wobbly nucleus. Cells solve this with dedicated nucleation machines. The Arp2/3 complex, found in organisms from yeast to humans, latches onto the side of an existing filament and spawns a new branch at a roughly 70-degree angle.7Trends in Cell Biology. Recent advances in Arp2/3 complex regulation Formins, by contrast, sit at the barbed end and catalyze elongation of straight, unbranched filaments that tend to grow faster and longer than Arp2/3-generated branches.8The Plant Cell. Cooperative actin filament nucleation by the Arp2/3 complex and formins maintains the homeostatic cortical array in Arabidopsis epidermal cells Between them, these two systems let a cell build architecturally distinct actin structures in different regions at the same time.
Cells also need to take filaments apart in a controlled way. Gelsolin, activated by calcium, can sever a filament mid-length and then cap the newly exposed barbed end, blocking further growth. Structural studies show that gelsolin’s six domains wrap around the filament in a way that distorts the contacts between neighboring subunits, snapping the chain.9PubMed Central. Mechanism of actin filament severing and capping by gelsolin Proteins like gelsolin let the cell rapidly remodel its actin skeleton in response to signals, rather than waiting for gradual treadmilling to do the job.
The Myosin Superfamily
Myosins are molecular motors. The typical myosin molecule has a head that binds both actin and ATP, a lever arm stiffened by small regulatory proteins called light chains, and a tail whose shape varies dramatically from one class to the next.10PubMed Central. Structural and functional insights on the Myosin superfamily That tail determines what the motor is used for: conventional muscle myosin (class II) has a long coiled-coil tail that bundles into thick filaments, while myosin V has a shorter tail with a cargo-binding domain that ferries vesicles along actin tracks.
Evolutionary analyses suggest that the ancestor of all modern eukaryotes already carried at least six myosin genes with distinct domain architectures. The biggest expansion of the family happened before animal multicellularity arose; single-celled relatives of animals turn out to have surprisingly elaborate myosin repertoires.11PubMed Central. Evolution and Classification of Myosins, a Paneukaryotic Whole-Genome Approach In other words, the molecular toolkit for force generation was well stocked long before complex tissues evolved to use it.
How Myosin Pulls on Actin
The engine of muscle contraction is the cross-bridge cycle, a repeating loop in which myosin heads attach to actin, pull, release, and reattach. Each complete cycle consumes one ATP molecule. When ATP binds, the myosin head releases actin. Hydrolysis of that ATP cocks the head into a pre-stroke position. The head then re-binds actin, and the release of phosphate triggers a conformational snap called the power stroke, which drags the actin filament a few nanometers. Modeling work has shown that one power stroke per ATP molecule is sufficient to explain the mechanical behavior observed in contracting muscle.12PubMed. On the regeneration of the actin-myosin power stroke in contracting muscle
An interesting feature is that the force a cross-bridge generates is directly tied to the strength of the bond between myosin and actin. That bond is driven by entropy rather than by the release of chemical energy in the usual sense, leading researchers to describe it as a thermal ratchet: random molecular jiggling is captured and converted into directed force each time the bond forms.13PubMed Central. The force exerted by a muscle cross-bridge depends directly on the strength of the actomyosin bond
Inside the Sarcomere
In striated muscle, actin and myosin filaments are arranged in a crystalline-like repeat called the sarcomere, held together by an elaborate protein scaffold.14PubMed. Architecture and function in the muscle sarcomere Thin filaments (actin) extend inward from each end, while thick filaments (myosin) occupy the center. When myosin heads pull the thin filaments toward the middle, the sarcomere shortens. Millions of sarcomeres shortening in series produce the visible contraction of a whole muscle.
In a relaxed heart muscle sarcomere, the myosin heads are not simply dangling. Cryo-electron microscopy has revealed that the two heads of each myosin molecule fold back on each other in an arrangement called the interacting heads motif. In this “off” state, one head blocks the actin-binding site of the other, keeping the motor quiet until it is needed.15Nature. Structure of the native myosin filament in the relaxed cardiac sarcomere
Calcium Turns Contraction On and Off
The on-off switch for striated muscle lives on the actin filament itself, in the form of two regulatory proteins: tropomyosin and troponin. At rest, when calcium levels in the cell are low, a segment of troponin pins tropomyosin in a position that physically covers the myosin-binding sites on actin.16PubMed Central. Mechanism of the calcium-regulation of muscle contraction–in pursuit of its structural basis When a nerve signal floods the muscle fiber with calcium, the ions bind to the troponin complex and cause part of it to release its grip on actin. Tropomyosin then slides into the groove of the actin helix, uncovering the binding sites and allowing cross-bridge cycling to begin.17PubMed Central. Structural basis for the activation of muscle contraction by troponin and tropomyosin The system is elegantly reversible: when calcium is pumped back out, troponin re-engages actin, tropomyosin slides back, and the muscle relaxes.18PubMed. Structural basis for Ca2+-regulated muscle relaxation at interaction sites of troponin with actin and tropomyosin
Splitting a Cell in Two
Every time one of your cells divides, actin and myosin cooperate to pinch the cell in half. A structure called the contractile ring assembles at the equator of the dividing cell, made of tightly packed, antiparallel actin filaments interspersed with chains of myosin II arranged head to head. Three-dimensional imaging shows this ring is strikingly similar to the stress fibers found in crawling cells, and it works like a purse string, tightening around the cell’s middle until the two daughter cells separate.19PubMed Central. The ultrastructural organization of actin and myosin II filaments in the contractile ring: new support for an old model of cytokinesis
Getting myosin to the right place at the right time involves at least two steps. First, signaling through a pathway involving the enzyme Rho kinase recruits myosin to the equatorial cortex. Then, formin-generated unbranched actin filaments are required to keep it there. Without those actin filaments, myosin drifts away from the equator and pops up unpredictably around the cell surface, causing abnormal blebbing rather than clean division.20PubMed Central. Distinct pathways control recruitment and maintenance of myosin II at the cleavage furrow during cytokinesis
Cell Migration and Mechanical Sensing
When a cell crawls, its leading edge pushes forward using a flat, fan-shaped sheet called a lamellipodium. Inside this sheet, the Arp2/3 complex generates a dense meshwork of branched actin that pushes against the membrane, while formins build the long parallel bundles that form finger-like filopodia at the front.21PubMed. Regulation of actin assembly associated with protrusion and adhesion in cell migration The orientation of actin in the lamellipodium matters: cancer cells exposed to an acidic environment, for example, reorganize their actin from a random arrangement into highly aligned bundles, and the cells become stiffer and more migratory as a result.22Frontiers in Physics. Effect of F-Actin Organization in Lamellipodium on Viscoelasticity and Migration of Huh-7 Cells Under pH Microenvironments Using AM-FM Atomic Force Microscopy
At the rear and flanks of a migrating cell, myosin II generates the contractile tension that retracts the tail and keeps the cell body moving forward. That same tension flows through focal adhesions, the molecular rivets linking the internal cytoskeleton to the external surface. Actomyosin contractility directly controls how quickly proteins turn over inside those adhesions: when myosin is inhibited, some adhesion proteins leave faster while others leave slower, triggering adhesion disassembly.23PubMed Central. Actomyosin-generated tension controls the molecular kinetics of focal adhesions Cells also sense the stiffness of their surroundings through this system. On stiffer substrates, both the overall pulling force and the tension within the adhesion protein vinculin increase, with the strongest forces concentrated near the cell edge.24Communications Biology. Linking molecular tension and cellular tractions: a multiscale approach to focal adhesion mechanics
Cargo Transport and Sensory Organs
Not all myosins work in large contractile arrays. Myosin V, for instance, is a long-legged motor that walks along actin filaments carrying membrane-bound parcels. It delivers endoplasmic reticulum vesicles in neurons, melanin-containing granules in pigment cells, and even the vacuole in yeast.25PubMed. Vesicle transport: the role of actin filaments and myosin motors In the brain, a specific variant called myosin Va ferries endoplasmic reticulum into the dendritic spines of cerebellar neurons, a step required for a form of synaptic weakening called long-term depression. A related motor, myosin Vb, delivers receptors into hippocampal spines to strengthen synapses during long-term potentiation.26Nature Reviews Neuroscience. Myosin motors at neuronal synapses: drivers of membrane transport and actin dynamics
In the inner ear, actin and myosin also play an essential structural role. The stereocilia that detect sound are stiff finger-like projections whose cores are made almost entirely of bundled actin filaments. These bundles are continuously maintained by controlled actin turnover, and mutations in several of the proteins involved cause deafness.27PubMed Central. Dynamic length regulation of sensory stereocilia A recent discovery shows that a specific myosin called MYO15A does not just walk along stereocilia actin but actively promotes the formation of new actin filaments. A deafness-causing mutation in its actin-binding site cripples this nucleation activity, and stereocilia fail to elongate properly.28Nature Communications. Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing The finding upends the assumption that myosin motors are purely force generators; at least one can also directly seed new cytoskeletal tracks.
Actin and Myosin Inside the Nucleus
For decades, actin and myosin were thought to be strictly cytoplasmic. That picture has changed. Both proteins are found inside the nucleus, where they participate in gene regulation and genome maintenance. Nuclear actin and myosins act as scaffolds and cross-linkers that connect distant regions of chromatin, influencing how tightly DNA is packed and which genes are accessible. A nuclear myosin called MVI anchors RNA polymerase II at transcription start sites, helping to organize clusters of active genes into so-called transcription factories.29PubMed Central. Actin from within – how nuclear myosins and actin regulate nuclear architecture and mechanics Disrupting nuclear actin or myosin does not just slow transcription; it appears to destabilize the genome broadly, affecting differentiation, development, and the cell’s ability to repair DNA damage.30PubMed. Nuclear actin and myosin in chromatin regulation and maintenance of genome integrity
When These Proteins Malfunction
Because actin and myosin are involved in so many processes, mutations in their genes cause a wide range of diseases. Mutations in the skeletal muscle actin gene ACTA1 produce at least two distinct muscle diseases: actin myopathy, in which excess thin filaments accumulate inside muscle fibers, and nemaline myopathy, characterized by abnormal rod-shaped protein aggregates. Both present with varying degrees of muscle weakness.31PubMed. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy
On the myosin side, the most medically significant example is hypertrophic cardiomyopathy, a condition in which the heart wall thickens abnormally. Mutations in the gene for cardiac beta-myosin heavy chain (MYH7) account for a substantial share of genetically identified cases.32PubMed. Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy A unifying hypothesis for how these mutations cause disease has gained strong support: rather than making individual myosin heads inherently stronger or faster, most mutations shift more myosin molecules from the folded “off” state into an active “on” state, producing a heart that contracts too forcefully.33PubMed Central. Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy This insight connects directly to the interacting heads motif described earlier: if the off-switch structure is destabilized by a mutation, too many heads become available to pull on actin at once.
Bacteria That Hijack the Actin System
Several disease-causing bacteria have evolved to exploit the host cell’s actin machinery for their own movement. The best-studied example is Listeria monocytogenes, the foodborne pathogen behind listeriosis. Once inside a host cell, Listeria displays a surface protein called ActA that mimics the host’s own actin-nucleation-promoting factors. ActA recruits the Arp2/3 complex plus accessory proteins like profilin and cofilin, assembling a comet-like tail of actin behind the bacterium that propels it through the cytoplasm and into neighboring cells.34PubMed. Host-pathogen interactions during entry and actin-based movement of Listeria monocytogenes The mimicry runs deep: the host kinase CK2 phosphorylates ActA at sites analogous to those it normally phosphorylates on the human WASP and WAVE proteins, fine-tuning ActA’s affinity for Arp2/3.35Cell Host & Microbe. Host Cell CK2-Mediated Phosphorylation of ActA Regulates Listeria monocytogenes Actin-Based Motility and Cell-to-Cell Spread Listeria is not alone; manipulating the actin cytoskeleton is a common virulence strategy across a variety of intracellular bacterial pathogens.36PubMed Central. Actin-based motility and cell-to-cell spread of bacterial pathogens
Drugs That Target Myosin and Emerging Biotech
The idea of directly targeting myosin with drugs has moved from academic curiosity toward clinical reality. For hypertrophic cardiomyopathy, the strategy is to push overactive myosin heads back into the off state. Moving in the other direction, a compound called CK-2018571 selectively inhibits smooth muscle myosin by trapping it during a transitional step of its mechanical cycle. Despite the fact that all of the drug’s binding-site residues are identical in smooth and skeletal muscle myosin, the compound achieves a selectivity difference of more than a thousand-fold between the two, exploiting a transient pocket that opens only in one motor type.37PubMed Central. Highly selective inhibition of myosin motors provides the basis of potential therapeutic application That level of selectivity matters: relaxing the smooth muscle in blood vessel walls without accidentally weakening the skeletal muscles you need to breathe is a non-trivial pharmacological challenge. Derivatives of blebbistatin, a widely used laboratory myosin inhibitor, are also being developed as potential treatments for conditions ranging from cancer metastasis to wound healing.38Trends in Biochemical Sciences. Recent advances in blebbistatin derivative development
Beyond medicine, the actomyosin system has caught the attention of bioengineers. In so-called in vitro motility assays, purified myosin is fixed to a surface and actin filaments are floated on top; the filaments glide along under their own molecular power. Researchers have achieved guided motion by patterning the surface with charged polymers, confining actin filaments to specific tracks at speeds of a few micrometers per second.39Nano Letters. Actomyosin-Driven Motility on Patterned Polyelectrolyte Mono- and Multilayers The long-term vision includes lab-on-a-chip devices that use actin filaments as nanoscale conveyor belts to transport molecular cargo through fabricated channels, and even network-based biocomputers that exploit filament movement to solve combinatorial problems.40PubMed Central. Improved longevity of actomyosin in vitro motility assays for sustainable lab-on-a-chip applications Whether these applications ever leave the lab depends on improving the longevity and reliability of the motor proteins on artificial surfaces, but the fact that biology’s own nanomotors can be repurposed at all is a testament to how robust the actin-myosin partnership really is.