Various Proteins Cross Link Intermediate Filaments to One Another and to Other Cell Structures

Intermediate filament-associated proteins (IFAPs) cross-link intermediate filaments with one another, forming a bundle or a network, and with other cell structures, including the plasma membrane. Only a few IFAPs have been identified to date, but many more will undoubtedly be discovered as researchers focus attention on the proteins that control IF organization and assembly. Unlike actin-binding proteins or microtubule-associated proteins, none of the known IFAPs sever or cap intermediate filaments, sequester IF proteins in a soluble pool, or act as a motor protein. Rather, IFAPs appear to play a role in organizing the IF cytoskeleton, integrating the IF cytoskeleton with both the microfilament and the microtubule cytoskeletons, and attaching the IF cy-toskeleton to the nuclear membrane and plasma membrane, especially at cell junctions.

A physical linkage between intermediate filaments and microtubules can be detected with certain drugs. Treatment of cells with high concentrations of colchicine causes the complete dissolution of microtubules after a period of several hours. Although vimentin filaments in colchicine-treated cells remain intact, they clump into disorganized bundles near the nucleus. This finding demonstrates that the organization of vimentin filaments is dependent on intact micro-tubules and suggests the presence of proteins linking the two types of filaments. In other studies, IFs have been shown to be cross-linked to actin filaments.

One family of IFAPs, the plakins, is responsible for linking IFs with both microtubules and microfilaments. One plakin family member is plectin, a 500,000-MW protein that has been shown to cross-link intermediate filaments with micro-tubules and actin filaments in vitro. Plectin also interacts with other cytoskeletal proteins, including spectrin, microtubule-associated proteins, and lamin B. Immunoelectron microscopy reveals gold-labeled antibodies to plectin decorating short, thin connections between microtubules and vimentin,

▲ EXPERIMENTAL FIGURE 19-35 Gold-labeled antibody allows visualization of plectin cross-links between intermediate filaments and microtubules. In this immunoelectron micrograph of a fibroblast cell, microtubules are highlighted in red; intermediate filaments, in blue; and the short connecting fibers between them, in green. Staining with goldlabeled antibodies to plectin (yellow) reveals that these fibers contain plectin. [From T M. Svitkina, A. B. Verkhovsky, and G. G. Borisy, 1996, J. Cell Biol. 135:991; courtesy of T M. Svitkina.]

indicating the presence of plectin in these cross-links (Figure 19-35). The N-terminus of plectin and other plakins contains a calponin-homology (CH) domain similar to that in fimbrin and other actin cross-linking proteins. This finding suggests that some plakins form cross-links between actin microfilaments and intermediate filaments.

Cross-links between microtubules and neurofilaments are seen in micrographs of nerve-cell axons (see Figure 19-32). Although the identity of these connections in axons is unknown, they may be IFAPs whose function is to cross-link neurofilaments and microtubules into a stable cytoskeleton. Alternatively, these connections to microtubules may be the long arms of NF-H, which is known to bind microtubules.

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