The cytoskeleton is a highly dynamic and organized network of filamentous proteins that extends throughout the cytoplasm. It provides mechanical support, determines cell shape, positions organelles, and generates the forces required for cell division and motility.
Actin Filaments (Microfilaments)
Actin filaments (F-actin) are 7 nm in diameter and assembled from globular actin (G-actin) monomers bound to either ATP or ADP. Polymerization occurs preferentially at the barbed (plus) end, while depolymerization occurs at the pointed (minus) end, a property called treadmilling when the rates are balanced. Actin-binding proteins regulate filament dynamics: profilin promotes actin polymerization by exchanging ADP for ATP, cofilin severs filaments and accelerates depolymerization, and the Arp2/3 complex nucleates new filaments as branches on existing ones. Capping proteins bind the barbed end to stabilize filaments, while tropomodulin caps the pointed end. Formins nucleate linear, unbranched filaments and remain associated with the barbed end during elongation.
Microtubules
Microtubules are hollow cylinders of 25 nm diameter composed of α- and β-tubulin heterodimers that assemble head-to-tail into protofilaments, typically thirteen of which form the microtubule wall. Microtubules exhibit dynamic instability: they alternate between phases of growth (polymerization of GTP-tubulin) and rapid shrinkage (catastrophe triggered by GTP hydrolysis in the β-tubulin subunit). The centrosome serves as the primary microtubule-organizing center in animal cells, containing a pair of centrioles surrounded by pericentriolar material rich in γ-tubulin ring complexes that nucleate microtubules. Microtubule-associated proteins (MAPs) such as MAP2 and tau stabilize microtubules, while katanin severs them. The drug taxol stabilizes microtubules and is used as a chemotherapy agent, while colchicine and nocodazole promote depolymerization.
Intermediate Filaments
Intermediate filaments are 10 nm in diameter and composed of diverse tissue-specific proteins. Cytoplasmic intermediate filaments include keratins in epithelial cells, vimentin in mesenchymal cells, desmin in muscle cells, glial fibrillary acidic protein in astrocytes, and neurofilaments in neurons. Nuclear intermediate filaments (lamins A, B, and C) form the nuclear lamina beneath the inner nuclear membrane, providing mechanical support for the nucleus and anchoring chromatin. Unlike actin and microtubules, intermediate filaments are non-polar and do not use nucleotide hydrolysis for polymerization. They provide mechanical resilience to cells and tissues, and mutations in intermediate filament genes cause diseases such as epidermolysis bullosa simplex (keratin), cardiomyopathy (desmin), and progeria (lamin A).
Motor Proteins
Myosins are actin-based motor proteins that move toward the barbed end of actin filaments (class II myosin in muscle, class V myosin in vesicle transport). Myosin II forms bipolar filaments that slide antiparallel actin filaments past each other, driving muscle contraction and cytokinesis. Kinesins are microtubule-based motors that typically move toward the plus end (toward the cell periphery), transporting vesicles, organelles, and mRNA along microtubule tracks. Dyneins are microtubule-based motors that move toward the minus end (toward the centrosome), powering retrograde axonal transport in neurons, positioning the Golgi apparatus, and driving ciliary and flagellar beating. Motor protein dysfunction leads to diseases such as amyotrophic lateral sclerosis (kinesin mutations) and primary ciliary dyskinesia (dynein mutations).
Cytoskeleton in Cell Division
During mitosis, the interphase microtubule array disassembles and is reorganized into the mitotic spindle, a bipolar array of microtubules that attach to chromosomes via kinetochores. The spindle assembly checkpoint ensures correct bipolar attachment before anaphase onset. Kinesin-5 (Eg5) crosslinks and slides antiparallel microtubules to separate the spindle poles. The actin cytoskeleton forms the contractile ring at the cleavage furrow during cytokinesis, consisting of actin filaments and myosin II that constrict to divide the cell. Midbody formation and abscission complete the separation of daughter cells.
Cell Motility and Migration
Cell migration is a cyclical process driven by actin dynamics. At the leading edge, the Arp2/3 complex and formins nucleate branched and linear actin networks that push the plasma membrane forward to form lamellipodia and filopodia. Focal adhesions connect the actin cytoskeleton to the extracellular matrix via integrins, providing traction. The cell body moves forward as actin-myosin contraction releases rear adhesions. Chemotaxis is directed cell migration along chemical gradients, mediated by GPCR signaling that activates PI3K, Rac, and Cdc42, which in turn regulate actin polymerization. Cells also move through three-dimensional environments using matrix metalloproteinases to degrade extracellular matrix or using amoeboid movement that squeeces through gaps.
