Intermediate filaments are a main component of the cytoskeleton. Their main function is to withstand mechanical stress, mainly stretching. This role is clear in animal cells. In plant cells, however, counteracting mechanical forces is carried out by the cell wall. Intermediate filament proteins have been found in plant cells, but their function is not fully understood. It is thought that intermediate filaments appeared in LECA (last eukaryote common ancestor), whereas other cytoskeletal proteins, such as tubulins and actin, arose in LUCA (last universal common ancestor), that is, the last common prokaryotic ancestor.
The diameter of intermediate filaments is 10 to 12 nm, between actin filaments (7 to 8 nm) and microtubules (25 nm). That is why the name intermediate. Initially, intermediate filaments were thought as leftovers of actin filaments and microtubules, so they were the last element to be considered as a cytoskeletal component. Intermediate filaments are found in animal cells, where they form a net that spreads from the nuclear envelope to the plasma membrane (Figure 1). They are usually anchored to adhesion cell complexes such as desmosomes, hemidesmosomes and focal adhesions. They are also found inside the nucleus forming the nuclear lamina, a scaffold of intermediate filaments that provides shape and consistence to the nuclear envelope. Intermediate filaments are abundant in those cells under heavy mechanical stress, such as neuronal axons, muscle cells, and epithelial cells.
1. Molecular structure
In humans, there are 70 genes coding for proteins that, after polymerization, become intermediate filaments. In addition, mRNA alternative splicing occurs in these genes giving to a broader protein variety. These proteins contain a globular domain in the C terminus end, another one in the N-terminus end, and, between them, a large central domain (Figure 2), altogether containing about 310-350 amino acids and are about 45 nm long. Globular domains are responsible for interacting with other cellular components and show the most variable part of the intermediate filament proteins. Globular domains also play a role in the spontaneous association between intermediate filament proteins. The central domain shows an α-helix structure, which allows the association of intermediate filament proteins to form dimers. Two dimers are associated laterally and anti-parallel by electrical forces to form tetramers, and tetramers join laterally to form a sheet of eight tetramers. This sheet rolls over itself (coiled structure of about 8 to 10 nm in diameter). In transfer view, an intermediate filament show 32 molecules. This structure lines up with other three to form a basic unit (around 60 nm in length; four tetramers in length), so that several basic units join by their ends to form intermediate filaments like long ropes. The different types of intermediate filaments show proteins with similar central domains, both in size and amino acid sequence.
2. Function
Intermediate filaments are flexible and resistant, two desirable features for withstanding mechanical stress. It is estimated that they can be stretched about 250 to 350 % of the resting length because protein units may slide one over the others, resulting in a smaller diameter of the filament. On the contrary, microtubules and actin filaments are quite stiff. Intermediate filaments are found from the cell periphery to the nucleus, therefore they are able to maintain the cell integrity. Besides resistance, intermediate filaments are involved in other cell functions. For example, they are proposed as anchoring structures for molecules involved in signaling. Furthermore, intermediate filaments form a molecular scaffold for cell organelles, and directly interact with mitochondria, Golgi apparatus, and lysosomes, so they may influence their functions and vesicular trafficking. For example, vimentin, a type of intermediate filament interacts with Rab proteins, which are involved in the delivery of vesicles and in the location of lysosomes.
Intermediate filaments are more stable during longer times than microtubules and actin filaments. They are also more resistant to high ionic concentrations. However, they can also be depolymerized and polymerized by phosphorylation and dephosphorylation, by kinases and phosphatases, respectively, as well as by the activity of some chaperones. There are a few proteins associated to intermediate filaments that influence their activity. Intermediate filaments can be renewed by removing and addition of new protein units. The intermediate filament scaffold can be reorganized under some circumstances, such as during cell movement, cell division, and when mechanical forces on cells change the direction. During tissue regeneration, cells near the wound show a different organization pattern of intermediate filament organization than those located at longer distances. During apoptosis, there is a reorganization of the cytoskeleton, intermediate filaments included, which is necessary for cell components degradation. Unlike the other two cytoskeletal members, intermediate filaments can not be used as transport pathways for molecules and organelles because they are not polarized, and there are no associated motor proteins. Actually, intermediate filaments are transported along microtubules and actin filaments.
3. Types
Intermediate filaments can be divided into 6 groups or classes.
Types I and II are acid and basic keratins, respectively. Both types combine between each other to form the cellular keratins, meaning that they are actually heterepolymeres. Keratins form a family of intermediate filaments having the most variable set of monomers. In humans, there are 54 genes synthesizing different keratin monomers, 28 belongs to type I and 26 to type II.
Keratins are abundant in epithelial cells. There are 17 different keratins in the hair and the rest of keratins are epithelial. Different sets of keratin are expressed depending on the epithelial type. For example, stratified squamous epithelium (excluding epidermis and cornea) does not express high molecular weigh keratins, which are present in the corneum stratum of the stratified squamous keratinized epithelium. There are also particular keratins in the hair, feathers and nails. Whatever the keratin type, it is formed by a mix of different keratin monomers.
Type III is composed of a heterogeneous population of intermediate filaments divided in four groups: vimentins, desmins, glial fibrilar acid proteins (GFAPs), and periferins. Vimentins are expressed in many cell types, such as messenchymal cells, leukocytes, endothelium and some other epithelial cells, usually together with other intermediate filaments. Vimentins are distributed through the cytoplasm and strongly interact with the nucleus. Desmins are main components of the cytoskeleton of the striated skeletal muscle cells. They are not found in myoblasts because they start to be expressed during the fusion of myoblasts to get differentiated muscle cells. Desmins are associated with Z discs of sarcomeres. Glial fibrilar acid proteins are expressed in astrocytes and other glial cells and are made up of just one type of protein. Peripherins are found in cranial nerves and peripheral neurons.
Type IV includes neurofilaments, found typically in neurons, syneimin, syncoilin and alpha-internexin. Regarding their molecular weight, they are classified as light, medium and heavy. Neurofilaments are expressed in mature neurons, are involved in the organization of dendrites and axons, and interact laterally with microtubules and actin filaments. They are made up of three types of monomeres.
Type V intermediate filaments are the nuclear lamins and they are the only type not found in the cytoplasm.
Type VI encompasses a new class of intermediate filaments containing the eye lens proteins such as filensin and phakinin. Nestins expressed in the proliferating nerve and muscle cells during development are also included.
Bibliography
Goldman RD, Grin B, Mendez MG, Kuczmarski ER. 2008. Intermediate filaments: versatile building blocks of cell structure. Current opinion in cell biology. 20:28-34. 
Margiotta A, Bucci C. 2016. Role of intermediate filaments in vesicular traffic. Cells 5, 20.
Microtubules 