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Intermediate filaments are important structural components of living cells. With the actin and tubulin systems, intermediate filaments make the third major filament system of the cytoskeleton. Intermediate filaments are essential for normal tissue structure and function; they provide physical resilience for cells to withstand the mechanical stresses of the tissue in which they are expressed. They are found in the nucleus (lamins) and the cytoplasm (cytoplasmic intermediate filaments) and take their name from their filament diameter, which at 8-12 nm is "intermediate" between that of muscle thin filaments (actin microfilaments at 4-6 nm) and thick filaments (bundles of myosin II).
Intermediate filaments are encoded in the human genome by 70 different genes in six subfamilies. This large multigene family is associated with 79 discrete clinical disorders, and the list is still growing. This curated Database aims to bring together basic information on this gene family and their associated sequence variations in humans.
Human intermediate filament gene symbols are ordered on the diagram below according to their positions on each chromosome. Gene and protein records can be accessed by clicking on individual gene symbol.
Each intermediate filament protein molecule has a long central α-helical region, the rod domain, flanked by a head (amino-terminal) and tail (carboxy-terminal) domain of more flexible and more variable structure. The α-helical rod domain of the intermediate filament proteins is between 300-330 (usually about 310) amino acids long, and is divided into four subdomains (1A, 1B, 2A, 2B) by three linker sequences (L1, L12, L2). There is also usually a recognizable discontinuity in the helix called the "stutter" (S is diagram) which may locally alter the character of the helix. The rod domain of lamin proteins (type V) is slightly longer. The α-helical subdomains are composed of sequential heptad repeating units containing hydrophobic residues at the first and fourth positions of every seven residues. This gives a hydrophobic strip down the helical cylinder of each coiled monomeric α-helical rod domain, which determines the tendency to dimerise as a coiled-coil. The formation of this extended rod structure is central to the nature and function of all intermediate filament proteins in vivo and in vitro.
The non-helical head (N-terminal) and tail (C-terminal) domains are usually made up of three distinguishable regions. These include: E1 (head) and E2 (tail), the extreme subdomains which are highly charged; V1 (head) and V2 (tail) are variable domains containing loose repeat sequence motifs - often similar in proteins expressed in similar tissue sites - and H1 (head) and H2 (tail) are "hypervariable" stretches that often contain phosphorylation target sites.
Fig. A: Diagram of intermediate filament protein domain structure. Rod domain labelled underneath; helix boundary motifs coloured in red.
Intermediate filaments are assembled from tetramers: two monomers form a parallel dimer by the winding of their α-helical rods into a coiled coil, oriented in register and in the same direction, and then two dimers join side-by-side in a staggered anti-parallel orientation to form a bidirectional tetramer. Each dimer is 48 nm long; because the dimers are staggered the tetramer is somewhat longer. The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments (which have a preferred assembly end), intermediate filaments do not show polarized unidirectional properties. Assembly and disassembly is regulated by cycles of phosphorylation and dephosphorylation; polymerization of intermediate filaments occurs rapidly and does not require cofactors or associated proteins.
Fig. B: Model summarizing current concepts of intermediate filament assembly. Drawn as for keratins, which assemble as type I/type II heteropolymers. Helix boundary peptides coloured red (helix initiation motif) and silver (helix termination motif). Head and tail domains not drawn: model only shows rod domains.
Some kinds of intermediate filaments interact with the plasma membrane. In epithelial cells, keratin filaments are attached by adapter proteins into desmosomes (cell-cell adhesion) and hemidesmosomes (cell-matrix adhesion). These junction proteins include plakoglobin, desmoplakin, desmogleins and desmocollins and others. Desmin filaments are similarly linked into cell-cell and cell-matrix anchorage junctions in heart muscle cells. Other known associated proteins include filaggrin, which binds to keratin filaments in differentiating epidermal cells, and plectin, isoforms of which connect intermediate filaments to microtubules and actin filaments.
Last modified: June 29 2007 17:05:54. |
