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intermediate filaments

Monday 10 November 2003

Cytoplasmic intermediate filaments (IF) can be divided into 5 subclasses based on their biochemical properties, immunologic specificity and tissue distribution: keratins in epithelial cells, vimentin, desmin in muscle cells, glial filaments (GFAP) in astrocytes, and neurofilaments in neurons. The different types of intermediate filament proteins share common structural features.

Intermediate filament proteins constitute a highly diverse family of fibrous proteins in metazoans, which assemble into 10-nm-thick filaments in the cytoplasm and the nucleus. The in vitro assembly mechanism have revealed principal differences in the formation of cytoplasmic and nuclear filaments.

Intermediate filaments are a structurally related family of cellular proteins that appear to be intimately involved with the cytoskeleton. The intermediate filaments are built up of rope-like polymers composed of protein subunits with linear a-helical content, and form a complex family of five different groups of filaments, one of which is the epithelial filaments.

Structure

The different sequence data show that the intermediate filament proteins contain a similar alpha-helical domain of conserved length capable of forming coiled-coils.

The common structural motif shared by all IFs is a central alpha-helical ’rod domain’ flanked by variable N- and C-terminal domains. The rod domain, the canonical feature of IFs, has been highly conserved during evolution. The variable terminals, however, have allowed the known IFs to be classified into 6 distinct types by virtue of their differing amino acid sequences.

Types

Types I and II

cytokeratins (keratins)

Type III

desmin
vimentin (MIM.193060)
GFAP (MIM.137780) (mutations in Alexander disease MIM.203450)
peripherin

Type IV

neurofilaments

Type V

nuclear lamins

Type VI

nestin (MIM.600915)

The vimentin, desmin, and glial fibrillary acidic protein genes each contains 8 introns at identical positions, 6 of the introns being located within the regions encoding alpha-helical sequences. A majority of the introns in the less closely related keratin genes occurred at similar or identical positions.

Localization

cytoplasmic filaments
nuclear filaments

Functions

Intermediate filament proteins (IFs) maintain cell and tissue integrity, based on evidence of their polymerization and mechanical properties, abundance and disease-associated phenotypes. This ’traditional’ function is now augmented by organelle-related and protein-targeting roles.

Mitochondrial location and function depend on intact IFs, as demonstrated for desmin, keratins and neurofilaments. Golgi positioning is regulated by several IFs, and endosomal/lysosomal protein distribution by vimentin.

IFs dramatically affect nuclear function and shape and play a role in subcellular and membrane targeting of proteins. These functions have been noted in tissues but in some cases only in cell culture.

The IF-related organelle-specific and protein-targeting roles, which are likely interrelated, provide functions beyond cell scaffolding and integrity and contribute to the cytoprotective and tissue-specific functions of IF proteins.

signal transduction

Pathology

intermediate filament-related dermatopathies (fibrillar dermatopathies)

pathology of cytokeratins (keratinopathies)

intermediate filament-related myopathies (myofibrillar myopathies)
intermediate filament-related neuropathies

intermediate filaments accumulations in amyotrophic lateral sclerosis (ALS) and neurodegeneration
neurofilament gene mutations linked to ALS and Charcot-Marie-Tooth disease (CMT2E)
GFAP mutations in Alexander disease

By systems

intermediate filaments in neuropathology

Five major types of intermediate filament proteins are expressed in mature neurons: the three neurofilament proteins (NF-L, NF-M, and NF-H), alpha-internexin, and peripherin.

intermediate filaments

B. Cellular pathology

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