Key Points
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Intermediate filaments (IFs) are assembled from fibrous proteins that exhibit a central α-helical rod domain with a conserved substructure. This rod domain facilitates the formation of dimeric coiled-coil complexes.
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In metazoan cells, IF proteins constitute two distinct filament systems: one in the nucleus and one in the cytoplasm. In both cases, the major function of these filaments is thought to be the buffering of mechanical stress.
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In conjunction with associated proteins, IFs generate networks that serve to generate and support the shape of cells.
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Recent nanomechanical experiments have demonstrated that IFs are characterized by a high propensity to withstand both tensile and bending stress.
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In line with this, disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of these diseases.
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Apart from structural functions, the analysis of complex diseases, such as cardiomyopathies, has revealed that IFs also have a significant role in cell-type-specific physiological functions and even contribute to the regulation of gene-expression programmes.
Abstract
Intermediate filaments (IFs) constitute a major structural element of animal cells. They build two distinct systems, one in the nucleus and one in the cytoplasm. In both cases, their major function is assumed to be that of a mechanical stress absorber and an integrating device for the entire cytoskeleton. In line with this, recent disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing. However, the analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions.
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Acknowledgements
The authors wish to acknowledge support from the German Research Foundation (H.H. and H.B.), the Swiss Society for Research on Muscular Diseases (U.A. and S.V.S.), the National Centre of Competence in Research program on 'Nanoscale Science', the Swiss National Science Foundation, the M.E. Müller Foundation of Switzerland and the Canton Basel-Stadt (all to U.A.), Group Biomedical Sciences and the Research Council of the Catholic University of Leuven (S.V.S.) and the European Union FP6 Life Science, Genomics and Biotechnology for Health area (H.H. and U.A.).
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DATABASES
OMIM
Hutchinson–Gilford progeria syndrome
FURTHER INFORMATION
Glossary
- Desmosome
-
A submembraneous, dense protein plaque that is composed of proteins such as desmoplakin to anchor intermediate filaments tightly. Desmosomes connect to identical structures of neighbouring cells via specific transmembrane proteins of the cadherin type.
- Adherens junction
-
A microfilament-anchoring plaque structure made from α- and β-catenin, plakoglobin and the C-terminal domains of classical cadherins, the extracellular domains of which bind in a calcium-dependent manner to similar proteins on neighbouring cells.
- Gap junction
-
A protein channel made from connexins that connects neighbouring cells and only lets pass molecules with a mass of ∼1,000 Da.
- Tight junction
-
A band-like, complex protein assembly that is built from polypeptides called claudins and occludins that resides in-between the plasma membranes of neighbouring cells. Tight junctions mediate a tight linkage of cell layers so that no solutes can pass.
- Microfilament
-
A cytoplasmic filament, with a 9-nm diameter, that is made from the globular protein actin. Depending on the cellular environment, microfilaments can be complexed with different sets of actin-binding proteins.
- Collagen
-
A fibril of high tensile strength made from hydroxyproline-rich triple-helical fibrous proteins. Collagen is the most abundant component in the extracellular matrix of metazoan cells.
- Hemidesmosome
-
A submembraneous plaque structure that connects the basal lamina via transmembrane proteins of the integrin type with intermediate filaments.
- Focal adhesion
-
A cell attachment and signalling structure that uses integrins to connect and integrate the extracellular matrix with the cytoplasmic microfilament system.
- Lamin
-
The nuclear intermediate filament protein that constitutes the basic structural element of the nuclear lamina; that is, the proteinaceous scaffold that supports the inner nuclear membrane and that connects it to chromatin.
- Heterochromatin
-
Segments of chromatin in eukaryotic cells that are highly condensed, transcriptionally repressed and that replicate late during interphase.
- MAN1
-
The MAN antigens are three inner nuclear membrane proteins that were discovered with the help of auto-antibodies isolated from a patient with a collagen vascular disease. MAN1 has the highest molecular weight (80,000 Da).
- Spectraplakin family
-
Multifunctional cross-bridging proteins, encoded by the BPAG1 and MACF1 genes, of up to 9,000 amino acids that share features with both the spectrin and plakin superfamilies and have many isoforms that are generated by differential splicing of their mRNAs.
- Costamere
-
A periodic rib-like region of the membrane cytoskeleton that contains actin-binding proteins such as vinculin, α- and β-spectrins, plectin and integrins. Costameres co-distribute with Z- and M-lines and provide a membrane linkage for the subsarcolemmal myofibrils. They are mechanically coupled to Z-disks by desmin filaments.
- Dynamic shear modulus
-
The shear modulus is a measure of the stiffness of a solid block when a force is applied parallel to one of its surfaces while the opposite surface is fixed to a support. When an oscillatory force is applied, a dynamic shear modulus is measured.
- Elastic modulus
-
For linearly elastic materials, the slope of the stress–strain curve is often referred to as the Young's modulus or the elastic modulus.
- Epidermolytic diseases
-
A group of inherited skin disorders that are characterized by blistering of the epidermis as a result of minor mechanical trauma. In these diseases, blister cleavage occurs in the plane of the epidermis.
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Herrmann, H., Bär, H., Kreplak, L. et al. Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol 8, 562–573 (2007). https://doi.org/10.1038/nrm2197
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DOI: https://doi.org/10.1038/nrm2197
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