Intermediate filaments, keratins

Cytokeratin Intermediate filament keratins found in epithelial tissue. There are two types of cytokeratins the acidic type 1 cytokeratins and the basic or neutral type 11 cytokeratins. Cytokeratins are thought to play a role in the activation of plasma prekallikrein and plasminogen. See Crewther, W.G., Fraser, R.D., Lennox, F.G., and Lindley, H., The chemistry of keratins, Adv. Protein Chem. 20, 191-346, 1965 Masri, M.S. and Friedman, M., Interactions of keratins with metal ions uptake profiles, mode of binding, and effects on the properties of wool, Arfv. Exp. Med. Biol. 48, 551-587,1974 Fuchs, E. and Green, H., Multiple keratins of cultured human epidermal cells are translated from different mRNA molecules. Cell 17, 573-582, 1979 ... 

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

North, A.C.T., Steinert, RM., Parry, D.A.D. Coiled-coil stutter and link segments in keratin and other intermediate filament molecules a computer modeling study. Proteins 20 174-184, 1994. 

Two major types of muscle fibers are found in humans white (anaerobic) and red (aerobic). The former are particularly used in sprints and the latter in prolonged aerobic exercise. During a sprint, muscle uses creatine phosphate and glycolysis as energy sources in the marathon, oxidation of fatty acids is of major importance during the later phases. Nonmuscle cells perform various types of mechanical work carried out by the structures constituting the cytoskeleton. These strucmres include actin filaments (microfilaments), micrombules (composed primarily of a- mbulin and p-mbulin), and intermediate filaments. The latter include keratins, vimentin-like proteins, neurofilaments, and lamins. 

In the keratins, large parts of the peptide chain show right-handed a-helical coiling. Two chains each form a left-handed superhelix, as is also seen in myosin (see p. 65). The superhelical keratin dimers join to form tetramers, and these aggregate further to form protofilaments, with a diameter of 3 nm. Finally, eight protofilaments then form an intermediate filament, with a diameter of 10 nm (see p.204). 

The components of the intermediate filaments belong to five related protein families. They are specific for particular cell types. Typical representatives include the cytokeratins, desmin, vimentin, glial fibrillary acidic protein (GFAP), and neurofilament. These proteins all have a rod-shaped basic structure in the center, which is known as a superhelix ( coiled coil see keratin, p. 70). The dimers are arranged in an antiparallel fashion to form tet-ramers. A staggered head-to-head arrangement produces protofilaments. Eight protofilaments ultimately form an intermediary filament. 

Keratin filaments are visible here in an epithelial cell. Keratin fibers belong to the group of intermediate filaments (see pp. 70, 204 d = nucleus). 

The principal cytoskeletal proteins in non-muscle cells are actin, tubulin, and the components of intermediate filaments. Actin can exist either as monomers ( G-actin ) or polymerized into 70 A diameter double filament ( F-actin ). Polymerized actin usually is localized at the margins of the cells, linked by other proteins to the cell membrane. In contrast, tubulin forms hollow filaments, approximately 250 A in diameter, that are distributed within a cell in association, generally, with cell organelles. Stabilized microtubule structures are found in the flagella and cilia of eucaryotic cells however, in other instances - examples being the mitotic apparatus and the cytoskeletal elements arising in directed cell locomotion - the microtubules are temporal entities. Intermediate filaments, which are composed of keratin-like proteins, are approximately 100 A thick and form stable structural elements that impart rigidity, for example, to nerve axons and epithelial cells. 

C4. Cauhn, C., Salvesen, G. S., and Oshima, R. G., Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithehal cell apoptosis. J. Cell Biol. 138,1379-1394 (1997). 

SUMMERHAYES, I.C., Cheng, Y.E., SuN, T.T., AND Chen, L.B. (1981). Expression of keratin and vimentin intermediate filaments in rabbit bladder epithelial cells at different stages of benzo[a]pyrene-induced neoplastic progression, J. Cell Bio. 90,63. 

An individual polypeptide in the a-keratin coiled coil has a relatively simple tertiary structure, dominated by an a-helical secondary structure with its helical axis twisted in a left-handed superhelix. The intertwining of the two a-helical polypeptides is an example of quaternary structure. Coiled coils of this type are common structural elements in filamentous proteins and in the muscle protein myosin (see Fig. 5-29). The quaternary structure of a-keratin can be quite complex. Many coiled coils can be assembled into large supramolecular complexes, such as the arrangement of a-keratin to form the intermediate filament of hair (Fig. 4-1 lb). 

FIGURE 4-11 Structure of hair, (a) Hair a-keratin is an elongated a helix with somewhat thicker elements near the amino and carboxyl termini. Pairs of these helices are interwound in a left-handed sense to form two-chain coiled coils. These then combine in higher-order structures called protofilaments and protofibrils. About four protofibrils—32 strands of a-keratin altogether—combine to form an intermediate filament. The individual two-chain coiled coils in the various substructures also appear to be interwound, but the handedness of the interwinding and other structural details are unknown, (b) A hair is an array of many a-keratin filaments, made up of the substructures shown in (a). 

Figure 7-31 A model for the structure of keratin microfibrils of intermediate filaments. (A) A coiled-coil dimer, 45-nm in length. The helical segments of the rod domains are interrupted by three linker regions. The conformations of the head and tail domains are unknown but are thought to be flexible. (B) Probable organization of a protofilament, involving staggered antiparallel rows of dimers. From Jeffrey A. Cohlberg297...

The two-stranded a-helical coiled coil is now recognized as one of natures favorite ways of creating a dimerization motif and has been predicted to occur in a diverse group of over 200 proteins.111 This structure consists of two amphipathic, right-handed a-helices that adopt a left-handed supercoil, analogous to a two-stranded rope where the nonpolar face of each a-helix is continually adjacent to that of the other helix. 2 This structure was first postulated by Crick to explain the X-ray diffraction pattern of a-keratin in the absence of sequence information.Pl The coiled-coil dimerization motif is natures way of creating a rod-like molecule that perhaps plays only a structural role in many fibrous proteins, such as the kmef (keratin, myosin, epidermis, fibrinogen) class 3,4 and the intermediate filament proteins)5 6 ... 

Steinert, P. M., Marekov, L. N., Fraser, R. D. B., and Parry, D. A. D. (1993a). Keratin intermediate filament structure Crosslinking studies yield quantitative information on molecular dimensions and mechanism of assembly. /. Mol. Biol. 230, 436-452. 

Candi, E., Tarcsa, E., DiGiovanna,J. J., Compton, J. G., Elias, P. M., Marekov, L. N., and Steinert, P. M. (1998). A highly conserved lysine residue on the head domain of Type II keratins is essential for the attachment of keratin intermediate filaments to the comified cell envelope through isopeptide crosslinking transglutaminases. Proc. Natl. Acad. Sci. USA 95, 2067-2072. 

Mack, J. W., Torchia, D. A., and Steinert, P. M. (1988). Solid-state NMR studies of the dynamics and structure of mouse keratin intermediate filaments. Biochemistry 27, 5418-5426. 

Parry, D. A. D., and North, A. C. T. (1998). Hard o-keratin intermediate filament chains Substructure of the N- and C-terminal domains and the predicted structure and function of the C-terminal domains of Type I and Type II chains./. Struct. Biol. 122, 67-75. 

Steinert, P. M., and Marekov, L. N. (1995). The Proteins elafin, filaggrin, keratin intermediate filaments, loricrin and small proline-rich proteins are isodipeptide cross-linked components of the human epidermal comified cell envelope. /. Biol. Chem. 270, 17702-17711. 

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