Intermediate filaments (IFs) are a component of the cytoskeleton - important structural components of living cells. Their size is intermediate between that of microfilaments and microtubules. They are assembled from several different proteins. IFs crisscross the cytosol from the nuclear envelope to the cell membrane.

Each IF molecule has a globular domain at both ends, separated by a long alpha-helical region. IFs are formed of dimers in which the two monomers are joined by the winding of their alpha-helical parts into a coiled coil, oriented in the same direction. Two dimers join side-by-side, antiparallel, forming a tetramer. Each dimer is 48 nanometers long but because the dimers are staggered, the tetramer is somewhat longer. The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments which have a plus end and a minus end, IFs lack polarity.

Although they cannot undergo treadmilling as microtubules and microfilaments, IFs are dynamic, continually disassembled into soluble tetramers and reassembled into filaments. Until 2003 IFs were thought to be static structural components. ^*

Types

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Different kinds of IFs share basic characteristics: they are all polymers that generally measure between 9-11 nm in diameter when fully assembled. IF are subcatagorized into five Types based on silimarlities in amino acid sequence and protein structure.

Types I and II - Acidic and Basic Keratins

These proteins are the most diverse among IFs and constitute type I (acidic) and type II (basic) IF proteins. The many isoforms are divided in two groups: epithelial keratins (about 20) in epithelial cells (image to right), and trichocytic keratins (about 13) (hair keratins) which make up hair, nails, horns and reptilian scales. Regardless of the group, keratins are either acidic or basic. Acidic and basic keratins bind each other to form acidic-basic heterodimers and these heterodimers then associate to make a keratin filament.

Type III

There are four proteins classed as type III IF proteins which may form homo- or heteropolymeric proteins.

• Desmin IFs are structural components of the sarcomeres in muscle cells.
• GFAP (glial fibrillary acidic protein) is found in astrocytes and other glia.
• Peripherin found in peripheral neurons.
• Vimentin, the most widely distribute of all IF proteins can be found in fibroblasts, leukocytes, and blood vessel endothelial cells. They support the cellular membranes and keep some organelles in a fixed place within the cytoplasm.

Type IV

• α-Internexin
• Nestin
• Neurofilament-L (designated NF-L for 'light')
• Neurofilament-M (designated NF-M for 'medium')
• Neurofilament-H (designated NF-H for 'heavy')
• Synemin
• Syncoilin

Neurofilaments are the type IV family of intermediate filaments that is found in high concentrations along the axons of vertebrate neurons. The three types of neurofilament proteins coassemble in vivo, forming a heteropolymer that contain NF-L plus one of the others. The NF-H and NF-M proteins have lengthy C-terminal tail domains that bind to neighboring filaments, generating aligned arrays with a uniform interfilament spacing. During axonal growth, new neurofilament subunits are incorporated all along the axon in a dynamic process that involves the addition of subunits along the filament length, as well as the addition of subunits at the filament ends. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold. The level of neurofilament gene expression seems to directly control axonal diameter, which in turn controls how fast electrical signals travel down the axon.^*

Axonal structure also depends on microtubules as well as actin filaments. Actin filaments line the cortex of the axon, just beneath the plasma membrane, and actin-based motor proteins such as myosin V are also abundant in the axon, perhaps to help move materials, although their exact function is still unclear. The specialized neurofilaments of nerve cells provide the most important structural support in the axon. A disruption in neurofilament structure, or in the cross-linking proteins that attach the neurofilaments to the microtubules and actin filaments distributed along the axon, can result in axonal disorganization and eventually axonal degeneration. ^*

Nestin is a type IV intermediate filament (IF) protein. It has never been shown to be capable of polymerizing into filaments alone, but is thought to require the presence of a type III or another type IV IF protein. Structuarally, nestin has the shortest head domain and the longest tail domain of all the IF. It is expressed by many types of cells during development, although its expression is usually transient and does not persist into adulthood. One instance of nestin expression in adult organisms, and perhaps that for which nestin is best know, are the neuronal precursor cells of the SVZ.

Plectin-like cross-links between microtubules and neurofilaments are seen in micrographs of nerve cell axons. They may represent intermediate filament associated proteins whose function is to cross-link neurofilaments and microtubules into a stable cytoskeleton. Alternatively, these connections to microtubules may be the long arms of the NF-H, which is known to bind microtubules. ^*

Type V - Nuclear Lamins

These proteins localize to two distict regions of the nuclear compartment. The first is the nuclear lamina, a proteinaceous layer located at the inner surface of the inner nuclear envelope membrane. The second is throughout the nucleoplasm in a structure termed the nucleoplasmic veil. Human cells express two types of lamin, A and B, from three differentially regulated genes. Lamin A and C are the most common A-type lamins and are splice variants of the LMNA gene found at 1q21. B type lamins, B1 and B2, are expressed from the LMNB1 and LMNB2 genes on 5q23 and 19q13, respectively.

Lamins are 10-13nm in length and have three central coiled-coil domains (a, b and c) that are organised around heptad repeats and separated by flexible linkers joining to make up an α-helical rod. Comparison of the lamins to vertebrate cytoskeletal IFs shows that lamins have an extra 42 residues (six heptads) within coil b. The central rod domain is flanked by a nuclear localization signal (NLS) and in most cases a carboxy-terminal CaaX box which can be isoprenylated and carboxymethylated.

Cell adhesion

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At the plasma membrane, some keratins interact with desmosomes (cell-cell adhesion) and hemidesmosomes (cell-matrix adhesion) via adapter proteins.

Associated proteins

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Filaggrin binds to keratin fibers in epidermal cells. Plectin links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin II.

Keratin filaments in epithelial cells link to desmosomes through plakoglobin, desmoplakin, desmogleins and desmocollins; desmin filaments are connected in a similar way in heart muscle cells.

Diseases arising from mutations in IF genes

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• Epidermolysis bullosa simplex; K5 or K14 mutation
• Laminopathies are a family of diseases caused by mutations in nuclear lamins and include Hutchinson Gilford Progeria Syndrome, Duchenne Muscular Dystrophy and various lipodystrophies and cardiomyopathies among others.

Cytoskeleton

Intermediální filamenta | Intermediärfilamente | 中間径フィラメント | Filamento intermedio