An intracellular fibrous system exists comprised of filaments with an axial periodicity of 21 nm and a diameter of 8 to 10 nm that is intermediate between that of microfilaments (6 nm) and microtubules (23 nm). At least four classes of intermediate filaments are found, as indicated in Table 1. Each is made up of elongated, fibrous molecules with a central rod domain, an amino-terminal head, and a carboxyl-terminal tail. These sub units assemble in a helical a manner to form repeating tetrameric units to form rope-like fibrils. Intermediate filaments are important structural components of cells that serve as relatively stable components of the cytoskeleton. Intermediate filaments are not undergoing rapid assembly and disassembly and not disappearing during mitosis, as do actin and many microtubular filaments. An important exception to this are the lamins, which, subsequent to phosphorylation, disassemble at mitosis and reappear when it terminates. Lamins form a meshwork positioned in apposition to the inner nuclear membrane. In addition, lamin A is an important component of the structural scaffolding that maintains the integrity of the cell nucleus.
Table1. Classes of Intermediate Filaments of Eukaryotic Cells & Their Distributions
Hutchinson-Gilford progeria syndrome (progeria, OMIM 176670) is caused by mutations in the LMNA gene that encodes lamin A and, via alternative splicing (see Chapter 36), lamin C. In progeria, a farnesylated form (see Figure 26–2 for the structure of farnesyl) of prelamin A accumulates in this condition, because the site at which the farnesylated portion of lamin A is normally cleaved by proteases has been altered by mutation. It appears that the accumulation of farnesylated prelamin A destabilizes nuclei, altering their shape, somehow predisposing victims to manifest signs of premature aging. Experiments in mice have indicated that administration of a farnesyltransferase inhibitor may ameliorate the development of misshapen nuclei. Children affected by this condition often die in their teens of atherosclerosis.
Keratins form a large family consisting of about 30 members. As indicated in Table 1, two major types of keratins are found that assemble into heterodimers made up of one member of each class. Vimentins are widely distributed in mesodermal cells. Desmin, glial fibrillary acidic protein, and peripherin are related to them. All members of the vimentin like family can copolymerize with each other.
Intermediate filaments in nerve cells, called neurofilaments, are classified as low, medium, and high on the basis of their molecular masses. The distribution of intermediate filaments in normal and abnormal (eg, cancer) cells can be studied by the use of immunofluorescent techniques. Pathologists utilize anti bodies against specific intermediate filaments to determine the origin of certain dedifferentiated malignant tumors.
A number of skin diseases, mainly characterized by blistering, have been found to be due to mutations in genes encoding various keratins. Two of these disorders are epidermolysis bullosa simplex (OMIM 131800) and epidermolytic palmoplantar keratoderma (OMIM 144200). The blistering found in these disorders probably reflects a diminished capacity of various layers of the skin to resist mechanical stresses due to abnormalities in the keratin structure.
