Intermediate filaments are a primary component of the cytoskeleton, although they are not found in all eukaryotes, and are absent in fungi and plants . These filaments, which extend throughout the cytoplasm and inner nuclear membrane are composed from a large family of proteins that can be broadly grouped into five classes.
IF assembly begins with the folding of IF proteins into a conserved alpha-helical rod shape, followed by a series of polymerization and annealing events that lead to the formation of filaments roughly 8 to 12 nm in diameter. Different IF combinations are found in different cell types, however not all IF classes will interact with each other. In contrast to other cytoskeletal components (e.g. actin filaments, microtubules), intermediate filaments lack polarity, are more stable and their constituent subunits do not bind nucleotides (such as ATP) (as reviewed in ).
The tight association between protofilaments provide intermediate filaments with a high tensile strength. This makes them the most stable component of the cytoskeleton. Intermediate filaments are therefore found in particularly durable structures such as hair, scales and fingernails.
The primary function of intermediate filaments is to create cell cohesion and prevent the acute fracture of epithelial cell sheets under tension. This is made possible by extensive interactions between the constituent protofilaments of an intermediate filament, which enhance its resistance to compression, twisting, stretching and bending forces. These properties also allow intermediate filaments to help stabilize the extended axons of nerve cells, as well as line the inner face of the nuclear envelope where they help harness and protect the cell’s DNA.
When compared to actin and tubulin, there is greater sequence variation within intermediate filament genes and the proteins they produce. This yields a greater diversity in the types of structures they can form (e.g. hair, nails, feathers, horns). Although different intermediate protein classes share a common ancestral origin, intermediate filament genes are only conserved in metazoans. Fungi and plants lack these filaments and insects have only one class . It seems likely that as the metazoan lineage evolved more intricate and complex tissues and organs, intermediate filaments were adapted and modified for tissue or cell specific purposes.
Intermediate filament subunits do not bind nucleotides and are oriented in opposite directions during filament assembly. This leads to a similar structural appearance at both the filament ends, as suggested by FRAP (fluorescence recovery after photobleaching) experiments . Furthermore subunit exchange is not confined to filament ends, as with microtubules and actin filaments, but occurs along the length of the filament .
The elastic nature of intermediate filaments is due the staggered assembly of their subunits into protofilaments and the high degree of lateral versus longitudinal interactions within the filaments. This structure promotes high tensile strength, toughness and long-range elasticity (reviewed in ).
No motor proteins have been identified to move along intermediate filaments as they lack polarity .
IFs exhibit a dynamic exchange of their constituent subunits, however this exchange rate is much slower than those observed with actin filaments or microtubules .
The soluble subunit for creating intermediate filaments is a tetramer. The tetramer is created from monomers in a stepwise fashion (as reviewed in ). First, two monomers associate via their central domains to form parallel helical coils around each other. This parallel dimer then associates with another parallel dimer in an antiparallel arrangement to form a staggered tetramer. The lateral association of eight tetramers results in the formation of a unit-length filaments (ULF). Two ULFs are able to anneal in an end-to-end fashion (i.e. longitudinally) to form a thick filament, approximately 16 nm in diameter. Further end-to-end annealing of ULFs results in filament elongation, which is followed by radial compaction to achieve the final intermediate filament diameter .
Keratin proteins comprise the two largest classes of intermediate filament proteins. Historically, the two types of keratin were grouped as acidic (type I) or basic (type II) according to the overall physical properties of their composite amino acids. Keratin proteins first assemble into dimers, with one acidic and one basic chain, then into protofilaments and finally into IFs. In 2006, a universal nomenclature for each of the then known keratin genes and proteins, which totaled 54 (28 type I and 26 type II), was established to achieve international consensus for their naming and classification .
The expression of particular acidic and basic keratins can be cell type specific. Keratins are found in epithelial tissues and their expression can be altered during the lifetime of a cell. Keratins provide vital internal support and cohesion to epithelial cell sheets. For example, the basal layer of epithelial cells that constantly divide and give rise to new skin cells (keratinocytes) become filled with keratin filaments as they mature. The keratin filaments anchor the skin cells to the extracellular matrix (ECM) at their base and to adjacent cells at their sides, through structures called hemidesmosomes and desmosomes, respectively. As these skin cells die, the layer of dead cells form an essential barrier to water loss. Consequently, mutations in keratin genes are known to be responsible for a variety of skin diseases. Keratin-containing structures are also located external to the epithelial cell layer (e.g. hair and nails).