Intermediate filament
Intermediate filament tail domain | |||||||||
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Intermediate filament rod domain | |||||||||
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Intermediate filament head (DNA binding) region | |||||||||
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Identifiers | |||||||||
Symbol | Filament_head | ||||||||
SCOP2 | 1gk7 / SCOPe / SUPFAM | ||||||||
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Peripherin neuronal intermediate filament protein | |||||||
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Identifiers | |||||||
Symbol | PRPH | ||||||
Alt. symbols | NEF4 | ||||||
Chr. 12 q13.12 | |||||||
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Nestin neuronal stem cell intermediate filament protein | |||||||
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Identifiers | |||||||
Symbol | NES | ||||||
Chr. 1 q23.1 | |||||||
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Intermediate filaments (IFs) are
Intermediate filaments are composed of a family of related
Structure
The structure of proteins that form intermediate filaments (IF) was first predicted by computerized analysis of the
The central building block of an intermediate filament is a pair of two intertwined proteins that is called a
Cytoplasmic IFs assemble into non-polar unit-length filaments (ULFs). Identical ULFs associate laterally into staggered, antiparallel, soluble tetramers, which associate head-to-tail into protofilaments that pair up laterally into protofibrils, four of which wind together into an intermediate filament.[13] Part of the assembly process includes a compaction step, in which ULF tighten and assume a smaller diameter. The reasons for this compaction are not well understood, and IF are routinely observed to have diameters ranging between 6 and 12 nm.
The N-terminus and the C-terminus of IF proteins are non-alpha-helical regions and show wide variation in their lengths and sequences across IF families. The N-terminal "head domain" binds
C-terminal "tail domain" shows extreme length variation between different IF proteins.[18]
The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments, which have a plus end and a minus end, IFs lack polarity and cannot serve as basis for cell motility and intracellular transport.
Also, unlike actin or tubulin, intermediate filaments do not contain a binding site for a nucleoside triphosphate.
Cytoplasmic IFs do not undergo treadmilling like microtubules and actin fibers, but are dynamic.[19]
Biomechanical properties
IFs are rather deformable proteins that can be stretched several times their initial length.
Types
There are about 70 different human genes coding for various intermediate filament proteins. However, different kinds of IFs share basic characteristics: In general, they are all polymers that measure between 9–11 nm in diameter when fully assembled.
Animal IFs are subcategorized into six types based on similarities in amino acid sequence and protein structure:[6]
Types I and II – acidic and basic keratins
These proteins are the most diverse among IFs and constitute
- epithelial keratins (about 20) in epithelialcells (image to right)
- trichocytic keratins (about 13) (hair keratins), which make up hair, nails, horns and reptilian scales.
Regardless of the group, keratins are either acidic or basic. Acidic and basic keratins bind each other to form acidic-basic heterodimers and these heterodimers then associate to make a keratin filament.[6]
Cytokeratin filaments laterally associate with each other to create a thick bundle of ~50 nm radius. The optimal radius of such bundles is determined by the interplay between the long range electrostatic repulsion and short range hydrophobic attraction.[21] Subsequently, these bundles would intersect through junctions to form a dynamic network, spanning the cytoplasm of epithelial cells.
Type III
There are four proteins classed as type III intermediate filament proteins, which may form
- Desmin IFs are structural components of the sarcomeres in muscle cells and connect different cell organells like the desmosomes with the cytoskeleton.[22]
- Glial fibrillary acidic protein (GFAP) is found in astrocytes and other glia.
- Peripherin found in peripheral neurons.
- endothelial cells. They support the cellular membranes, keep some organelles in a fixed place within the cytoplasm, and transmit membrane receptor signals to the nucleus.[6]
- Syncoilin is an atypical type III IF protein.[23]
Type IV
- Alpha-internexin
- Neurofilaments – the type IV family of intermediate filaments that is found in high concentrations along the axons of vertebrate neurons.
- Synemin
- Syncoilin
Type V – nuclear lamins
Lamins are fibrous proteins having structural function in the cell nucleus.
In metazoan cells, there are A and B type lamins, which differ in their length and pI. Human cells have three differentially regulated genes. B-type lamins are present in every cell. B type lamins, lamin B1 and B2, are expressed from the LMNB1 and LMNB2 genes on 5q23 and 19q13, respectively. A-type lamins are only expressed following gastrulation. Lamin A and C are the most common A-type lamins and are splice variants of the LMNA gene found at 1q21.
These proteins localize to two regions of the nuclear compartment, the nuclear lamina—a proteinaceous structure layer subjacent to the inner surface of the nuclear envelope and throughout the nucleoplasm in the nucleoplasmic veil.
Comparison of the lamins to vertebrate cytoskeletal IFs shows that lamins have an extra 42 residues (six heptads) within coil 1b. The c-terminal tail domain contains a nuclear localization signal (NLS), an Ig-fold-like domain, and in most cases a carboxy-terminal CaaX box that is isoprenylated and carboxymethylated (lamin C does not have a CAAX box). Lamin A is further processed to remove the last 15 amino acids and its farnesylated cysteine.
During mitosis, lamins are phosphorylated by MPF, which drives the disassembly of the lamina and the nuclear envelope.[6]
Type VI
- Beaded filaments: Filensin, Phakinin.[6]
- Nestin (was once proposed for reclassification but due to differences, remains as a type VI IF protein)[24]
Vertebrate-only. Related to type I-IV. Used to contain other newly discovered IF proteins not yet assigned to a type.[25]
Function
Cell adhesion
At the
Associated proteins
Filaggrin binds to keratin fibers in epidermal cells. Plectin links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin II. Kinesin is being researched and is suggested to connect vimentin to tubulin via motor proteins.
Keratin filaments in epithelial cells link to desmosomes (desmosomes connect the cytoskeleton together) through plakoglobin, desmoplakin, desmogleins, and desmocollins; desmin filaments are connected in a similar way in heart muscle cells.
Diseases arising from mutations in IF genes
- Dilated cardiomyoathy (DCM), mutations in the DES gene[26]
- Arrhythmogenic cardiomyopathy (ACM), mutations in the DES gene[27][28][29][30]
- Restrictive cardiomyopathy (RCM), mutations in the DES gene[31]
- Non-compaction cardiomyopathy, mutations in the DES genes[32][33]
- Cardiomyopathy in combination with skeletal myopathy (DES)[34]
- Epidermolysis bullosa simplex; keratin 5 or keratin 14 mutation
- Hutchinson-Gilford progeria syndromeand various lipodystrophies and cardiomyopathies among others.
In other organisms
IF proteins are universal among animals in the form of a nuclear lamin. The Hydra has an additional "nematocilin" derived from the lamin. Cytoplasmic IFs (type I-IV) are only found in Bilateria; they also arose from a gene duplication event involving "type V" nuclear lamin. In addition, a few other diverse types of eukaryotes have lamins, suggesting an early origin of the protein.[25]
There was not really a concrete definition of an "intermediate filament protein", in the sense that the size or shape-based definition does not cover a
References
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Further reading
- Herrmann H, Harris JR, eds. (1998). Intermediate filaments. Springer. ISBN 978-0-306-45854-5.
- Omary MB, Coulombe PA, eds. (2004). Intermediate filament cytoskeleton. Gulf Professional Publishing. ISBN 978-0-12-564173-9.
- Paramio JM, ed. (2006). Intermediate filaments. Springer. ISBN 978-0-387-33780-7.
External links
- Intermediate+Filament+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)