Intermediate Filament Proteins and Their Associated Diseases

he cytoskeleton consists of three abundant families of fibrillary proteins: microfilaments, microtubules, and intermediate filaments. ntermediate filament proteins derive their name from their diameter, which is intermediate between the diameters of microfilaments and microtubules. 1,2 2] More than 30 diseases are related to mutations in these genes (Table The majority of them are rare (affecting fewer than 200,000 patients in the United States) or difficult to treat, 7 but collectively they affect most tissues, and not all of them are rare, as exemplified by the association of keratin mutations with end-stage liver disease. Intermediate filament proteins have long been considered unique to multicellular eukaryotic organisms, 8 in contrast to microfilaments and microtubules, which have prokaryotic ancestors. However, crescentin, which is found in several curved bacteria, including Caulobacter crescentus and Helicobacter pylori, was recently identified as an intermediate filament-like ancestor protein that accounts for the morphologic features of caulobacter. 9 structure All intermediate filament proteins have a prototypical structure consisting of a coiledcoil, a -helix rod domain (two polypeptide a -helixes wound around each other) that is interrupted by linkers and flanked by N-terminal head and C-terminal tail domains (Fig. The simplest soluble unit of intermediate filament proteins is a tetramer consisting of two antiparallel dimers; each dimer, in the case of keratins, consists of one type I keratin molecule and one type II keratin molecule. A high-resolution architectural model of intermediate filaments is lacking, although the mature, 10-to-12-nm fiber is believed to contain 32 monomers in diameter, with important structural polymorphisms among members of the protein family. 2,3 Cytoplasmic intermediate filaments can assume various network configurations depending on the cell type and manifest variable differentiation-related patterns, such as those in apical poles (e.g., pancreatic keratins), Z lines (desmin), and axonal processes (neurofilaments). 2,3,10 regulation Intermediate filament proteins are regulated by several post-translational modifications, including farnesylation, phosphorylation, glycosylation, and transglutamination, t general features of intermediate filaments