Intermediate filaments: versatile building blocks of cell structure

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Cytoskeletal intermediate filaments (IF) are organized into a dynamic nanofibrillar complex that extends throughout mammalian cells. This organization is ideally suited to their roles as response elements in the subcellular transduction of mechanical perturbations initiated at cell surfaces. IF also provide a scaffold for other types of signal transduction that together with molecular motors ferries signaling molecules from the cell periphery to the nucleus. Recent insights into their assembly highlight the importance of co-translation of their precursors, the hierarchical organization of their subunits in the formation of unit-length filaments (ULF) and the linkage of ULF into mature apolar IF. Analyses by atomic force microscopy reveal that mature IF are flexible and can be stretched to over 300% of their length without breaking, suggesting that intrafilament subunits can slide past one another when exposed to mechanical stress and strain. IF also play a role in the organization of organelles by modulating their motility and providing anchorage sites within the cytoplasm.

Introduction

Intermediate filaments (IF) assemble into extensive cytoskeletal networks that appear to connect the cell surface with the nucleus and provide cells with important mechanical properties (Figure 1, Figure 2 [1, 2]). At the cell surface, IF interact with desmosomes, hemidesmosomes, focal adhesions and the extracellular matrix via a variety of linker proteins [3, 4, 5]. There is also evidence that IF associate with factors on the outer nuclear membrane that, in turn, connect to components of the nuclear lamina [4, 6]. These observations suggest that IF form a continuous network of nanofibrils along which signals from the cell's exterior can be transmitted to the nuclear surface and the nucleoplasm. The extensive distribution of IF provides an enormous surface area that can act as a scaffold for the binding of numerous types of regulatory and signaling molecules [7, 8]. The IF system has also been shown to associate with membranous organelles such as mitochondria, the Golgi apparatus and vesicles, as well as with other cytoskeletal components such as actin filaments, microtubules and their associated molecular motors [4, 6, 9]. Thus, the IF system is positioned to perform significant roles in the internal organization and positioning of organelles and other cytoplasmic components. In humans, over 70 genes encode the protein subunits that assemble into the 10–12 nm filaments located in the cytoplasm [10]. The expression of these subunits is developmentally regulated and subunits are frequently mixed and matched. IF protein subunits are therefore the building blocks of a potentially enormous variety of protein polymers that serve as customized scaffolding materials in different cell types.

Section snippets

Recent insights into intermediate filament structure and assembly

All IF proteins have similar structural features; a conserved central α-helical rod domain flanked by non-α-helical N-(head) and C-terminal (tail) domains. The central rod is composed mainly of seven-residue repeats (heptad repeats) that enable the formation of a coiled-coil structure [11]. The non-α-helical head and tail domains are variable in size and sequence, contributing to the diversity of the IF superfamily.

Intermediate filament proteins interact to form coiled-coil dimers in different

Intermediate filaments: structure and nanomechanics

In vitro studies have revealed that the properties of IF are uniquely adapted for dealing with mechanical stress. Intermediate filaments are both strong and flexible polymers. Previous studies have shown that vimentin IF networks reconstituted in vitro can withstand strains of over 100% without losing their elasticity. In fact, the more the vimentin networks are strained, the more resistant they become to further deformation. This behaviour is referred to as ‘strain stiffening’ [28].

Intermediate filaments: roles in mechano-transduction and signaling

The mechanical properties of IF in vitro and the fact that in most cells they form interacting networks between the cell surface and the nucleus (Figure 1, Figure 2) lead to the hypothesis that this system provides tracks or scaffolds for the transduction of mechanical perturbations in a cell's environment throughout all compartments of the cell. There is some evidence in support of this hypothesis in vascular endothelial cells subjected to shear stress across their surfaces. These cells

IF and the cytoplasmic organization of organelles: possible roles in tethering and positioning

Although there is a significant literature on the interactions between IF and membranous organelles, little attention has been paid to this important area of research until quite recently. It has been known for many years that IF, as well as microtubules, interact with membranous organelles such as mitochondria, the Golgi complex and more recently, lysosomes. Mitochondrial associations with vimentin IF were first described by electron microscopy (e.g. [39, 40]). In nerve cells, the subcellular

Conclusions

Intermediate filaments play a key role in establishing and maintaining the mechanical integrity of cells. Recent studies in vitro have provided insights into the molecular mechanisms responsible for IF assembly, revealing their unique structure that resembles cables or ropes assembled from numerous repeating rod-like elements. Studies of single intermediate filaments reveal that this organization results in very flexible filaments that can be stretched several fold before they break. When

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The work described in this publication was supported by grants to RDG from the National Institutes of Health (General Medical Sciences #GM36806; Heart, Lung and Blood Institute #HL071643).

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