INTERMEDIATE FILAMENTS: STRUCTURE, TYPES, FUNCTIONS - BIOLOGY - 2025

The intermediate filaments, also known in the literature as "IFs" (of the English Intermediate filaments), are a family of fibrous proteins cytosolic insolubles are present in all cells of multicellular eukaryotes.

They are part of the cytoskeleton, which is an intracellular filamentous network that is mainly responsible for the support of the cell structure and various metabolic and physiological processes such as vesicle transport, cell movement and displacement, etc.

Immunofluorescence microscopy of two proteins of the intermediate filaments of astrocytes (Vimentin and GFAP) (Source: GerryShaw via Wikimedia Commons)

Along with microtubules and microfilaments, intermediate filaments participate in the spatial organization of intracellular organelles, in the processes of endocytosis and exocytosis, and also in the processes of cell division and intercellular communication.

The first intermediate filaments to be studied and described were keratins, one of the first types of proteins whose structure was analyzed by X-ray diffraction in the 1930s.

The concept of intermediate filaments, however, was introduced in the 1980s by Lazarides, who described them as complex "mechanical integrators of the cell space", characterized by their insolubility and their ability to reassemble in vitro after denaturation.

They are considered by many authors as stress "buffer" elements for animal cells, since they are more flexible filaments than microtubules and microfilaments. They are not only found in the cytoskeleton, but they are also part of the nucleoskeleton.

Unlike the other fibrous components of the cytoskeleton, the intermediate filaments do not participate directly in the processes of cell mobility, but rather function in the structural maintenance and mechanical resistance of cells.

Structure

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The intermediate filaments have an approximate diameter of 10 nm, a structural characteristic for which they were named, since their size is between the sizes corresponding to myosin and actin filaments, which are between 25 and 7 nm. respectively.

They differ structurally from the other two types of cytoskeletal filaments, which are globular protein polymers, in that their constituent units are distinct long-length α-helical fibrous proteins that cluster together to form rope-like structures.

All the proteins that make up the intermediate filaments have a similar molecular organization, consisting of an α-helical or "rope" domain that has different amounts of "coil-forming" segments of the same size.

This helical domain is flanked by an N-terminal non-helical "head" and a non-helical "tail" at the C-terminal end, both of which vary in both size and amino acid sequence.

Within the sequence of these two ends are the consensus motifs that are common for the 6 types of intermediate filaments known.

In vertebrates, the "chord" domain of cytosolic intermediate filament proteins is about 310 amino acid residues, while invertebrate and nuclear lamina cytosolic proteins are roughly 350 amino acids long.

Assembly

Intermediate filaments are "self-assembling" structures that do not possess enzymatic activity, which also differentiates them from their cytoskeletal counterparts (microtubules and microfilaments).

These structures are initially assembled as tetramers of the filamentous proteins that make them up under the influence only of monovalent cations.

These tetramers are 62 nm long and their monomers associate with each other laterally to form unit-length filaments (UFL), known as phase 1 of assembly, which occurs very rapidly..

The UFLs are the precursors of long filaments and, since the dimers that make them up are joined together in an antiparallel and staggered manner, these units have a central domain with two flanking domains through which phase 2 of elongation occurs., where the longitudinal union of other UFLs occurs.

During what has been termed as phase 3 of the assembly, radial compaction of the diameter of the filaments occurs, which produces mature intermediate filaments of more or less 10 nm in diameter.

Features

The functions of the intermediate filaments depend considerably on the type of cell considered and, in the case of animals (including humans), their expression is regulated in a tissue-specific way, which is why it also depends on the type of tissue than in study.

Epithelia, muscles, mesenchymal and glial cells and neurons have different types of filaments, specialized according to the function of the cells to which they belong.

Among these functions, the most important are the structural maintenance of cells and resistance to different mechanical stresses, since these structures have a certain elasticity that allows them to cushion different types of forces imposed on the cells.

Types of intermediate filaments

The proteins that make up the intermediate filaments belong to a large and heterogeneous family of filamentous proteins that are chemically different but that are distinguished into six classes according to their sequence homology (I, II, III, IV, V and VI).

Although it is not very common, different types of cells, under very particular conditions (development, cell transformation, growth, etc.) can co-express more than one class of intermediate filament-forming proteins

Class I and II intermediate filaments: acidic and basic keratins

Keratins represent the majority of the proteins in the intermediate filaments and, in humans, they represent more than three-quarters of the intermediate filaments.

They have molecular weights that vary between 40 and 70 kDa and differ from other intermediate filament proteins by their high content of glycine and serine residues.

They are known as acidic and basic keratins because of their isoelectric points, which are between 4.9 and 5.4 for acidic keratins and between 6.1 and 7.8 for basic ones.

In these two classes, around 30 proteins have been described and are present especially in epithelial cells, where both types of proteins "co-polymerize" and form compound filaments.

Many of the intermediate filament case I keratins are found in structures such as hair, nails, horns, spikes, and claws, while those of class II are the most abundant in the cytosol.

Class III intermediate filaments: Desmin / vimentin type proteins

Desmin is a 53 kDa acidic protein that, depending on its degree of phosphorylation, has different variants.

Some authors have also called desmin filaments "intermediate muscle filaments", since their presence is quite restricted, although in small quantities, to all types of muscle cells.

In myofibrils, desmin is found in the Z line, so it is thought that this protein contributes to the contractile functions of muscle fibers by functioning at the junction of myofibrils and the plasma membrane.

Photograph of the staining of the protein Vimentin, a protein of the intermediate filaments of epithelial and embryonic cells (Source: Viktoriia Kosach via Wikimedia Commons)

In turn, vimentin is a protein present in mesenchymal cells. The intermediate filaments formed by this protein are flexible and have been found to resist many of the conformational changes that occur during the cell cycle.

It is found in fibroblasts, smooth muscle cells, white blood cells, and other cells in the circulatory system of animals.

Class IV intermediate filaments: neurofilament proteins

Also known as "neurofilaments", this class of intermediate filaments comprises one of the fundamental structural elements of neuronal axons and dendrites; they are often associated with the microtubules that also make up these structures.

The neurofilaments of vertebrate animals have been isolated, determining that it is a triplet of proteins of 200, 150 and 68 kDa that participate in the assembly in vitro.

They differ from other intermediate filaments in that they have lateral arms as "appendages" that project from the periphery of the same and that function in the interaction between neighboring filaments and other structures.

Glial cells produce a special type of intermediate filaments known as glial intermediate filaments, which differ structurally from neurofilaments in that they are composed of a single 51 kDa protein and have different physicochemical properties.

Intermediate filament class V: nuclear lamina filaments

All the laminae that are part of the nucleoskeleton are actually intermediate filament proteins. These are between 60 and 75 kDa in molecular weight and are found in the nuclei of all eukaryotic cells.

They are essential for the internal organization of the nuclear regions and for many of the functions of this organelle essential for the existence of eukaryotes.

Intermediate filament class VI: Nestinas

This type of intermediate filament weighs about 200 kDa and is predominantly found in stem cells of the central nervous system. They are expressed during neuronal development.

Related pathologies

There are multiple diseases in humans that are related to intermediate filaments.

In some types of cancer such as malignant melanomas or breast carcinomas, for example, the co-expression of intermediate filaments of vimentin and keratin leads to the differentiation or interconversion of epithelial and mesenchymal cells.

This phenomenon has been shown experimentally to increase the migratory and invasive activity of cancer cells, which has important implications for the metastatic processes characteristic of this condition.

Eriksson et al. (2009) review the different types of diseases and their relationship with specific mutations in the genes involved in the formation of the six types of intermediate filaments.

Diseases associated with mutations in the genes encoding the two types of keratin are epidermolysis bullosa, epidermolytic hyperkeratosis, corneal dystrophy, keratoderma, and many others.

Type III intermediate filaments are involved in numerous cardiomyopathies and in different muscular diseases mainly related to dystrophies. In addition, they are also responsible for dominant cataracts and some types of sclerosis.

Many neurological syndromes and disorders are associated with type IV filaments, such as Parkinson's. In the same way, genetic defects in type V and VI filaments are responsible for the development of different autosomal diseases and related to the functioning of the cell nucleus.

Examples of these are Hutchinson-Gilford progeria syndrome, Emery-Dreifuss muscular dystrophy, among others.

References

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