Intermediate filament
Encyclopedia
Intermediate filaments (IFs) are a family of related protein
s that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin
(microfilament
s), and that of 25 nm microtubule
s, although they were initially designated 'intermediate' because their average diameter is between those of narrower microfilament
s (actin) and wider myosin
filaments. Most types of intermediate filaments are cytoplasm
ic, but one type, the lamins, are nuclear.
. The dimer is formed through the interaction of the rod domain to form a coiled coil
. Cytoplasmic IF assemble into non-polar unit-length filaments (ULF), which then assemble into longer structures. 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-terminal "head domain" binds DNA
. Vimentin
heads are able to alter nuclear
architecture and chromatin
distribution, and the liberation of heads by HIV-1 protease
may play an important role in HIV-1 associated cytopathogenesis and carcinogenesis
. Phosphorylation
of the head region can affect filament stability. The head has been shown to interact with the rod domain of the same protein
.
C-terminal "tail domain" shows extreme length variation between different IF proteins.
The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments, which have a plus end and a minus end, IFs lack polarity.
Also, as opposed to actin
or tubulin
, intermediate filaments do not contain a binding site
for a nucleoside triphosphate
.
Cytoplasmic IF do not undergo treadmilling
like microtubules and actin fibers, but they are dynamic. For a review see: http://jcs.biologists.org/cgi/content/full/117/2/133.
IF are subcategorized into six types based on similarities in amino acid sequence and protein
structure.
These proteins are the most diverse among IFs and constitute type I (acidic)
and type II (basic)
IF proteins. The many isoforms are divided in two groups:
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.
ic proteins.
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, 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.
s (cell-cell adhesion) and hemidesmosome
s (cell-matrix adhesion) via adapter proteins.
binds to keratin fibers in epidermal cells. Plectin
links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin
II.
Keratin filaments in epithelial cells link to desmosome
s (desmosomes connect the cytoskeleton together) through plakoglobin
, desmoplakin
, desmoglein
s, and desmocollin
s; desmin
filaments are connected in a similar way in heart muscle cells.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
(microfilament
Microfilament
Microfilaments are the thinnest filaments of the cytoskeleton, a structure found in the cytoplasm of all eukaryotic cells. These linear polymers of actin subunits are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton...
s), and that of 25 nm microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s, although they were initially designated 'intermediate' because their average diameter is between those of narrower microfilament
Microfilament
Microfilaments are the thinnest filaments of the cytoskeleton, a structure found in the cytoplasm of all eukaryotic cells. These linear polymers of actin subunits are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton...
s (actin) and wider myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
filaments. Most types of intermediate filaments are cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic, but one type, the lamins, are nuclear.
Structure
The domain structure of IF molecules is conserved. Each protein has a non-alpha-helical (globular) domain at the N and C-termini, which surrounds the alpha-helical rod domain. The basic building-block for IFs is a parallel and in-register dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
. The dimer is formed through the interaction of the rod domain to form a coiled coil
Coiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
. Cytoplasmic IF assemble into non-polar unit-length filaments (ULF), which then assemble into longer structures. 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-terminal "head domain" binds DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
heads are able to alter nuclear
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
architecture and chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
distribution, and the liberation of heads by HIV-1 protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
may play an important role in HIV-1 associated cytopathogenesis and carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
. Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the head region can affect filament stability. The head has been shown to interact with the rod domain of the same protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
.
C-terminal "tail domain" shows extreme length variation between different IF proteins.
The anti-parallel orientation of tetramers means that, unlike microtubules and microfilaments, which have a plus end and a minus end, IFs lack polarity.
Also, as opposed to actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
or tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
, intermediate filaments do not contain a binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
for a nucleoside triphosphate
Nucleoside triphosphate
Nucleoside triphosphate is a nucleoside with three phosphates. Natural nucleoside triphosphates include adenosine triphosphate , guanosine triphosphate , cytidine triphosphate , 5-methyluridine triphosphate , and uridine triphosphate . These terms refer to those nucleoside triphosphates that...
.
Cytoplasmic IF do not undergo treadmilling
Treadmilling
Treadmilling is a phenomenon observed in many cellular cytoskeletal filaments, especially in actin filaments and microtubules. It occurs when one end of a filament grows in length while the other end shrinks resulting in a section of filament seemingly "moving" across a stratum or the cytosol...
like microtubules and actin fibers, but they are dynamic. For a review see: http://jcs.biologists.org/cgi/content/full/117/2/133.
Biomechanical properties
IFs are rather deformable proteins that can be stretched several times their initial length. The key to facilitate this large deformation is due to their hierarchical structure, which facilitates a cascaded activation of deformation mechanisms at different levels of strain.Types
There are about 70 different 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.IF are subcategorized into six types based on similarities in amino acid sequence and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
structure.
Types I and II - Acidic and Basic Keratins
These proteins are the most diverse among IFs and constitute type I (acidic)
Type I cytokeratin
Type I keratins constitutes the Type I intermediate filaments of the intracytoplasmatic cytoskeleton, which is present in all mammalian epithelial cells...
and type II (basic)
Type II cytokeratin
Type II keratins constitutes the Type II intermediate filaments of the intracytoplasmatic cytoskeleton, which is present in all mammalian epithelial cells...
IF proteins. The many isoforms are divided in two groups:
- epithelial keratins (about 20) in epithelial cells (image to right)
- trichocytic keratins (about 13) (hair keratinHair keratinHair keratin is a type of keratin found in hair and nails. There are two types of hair keratin:* the acidic type I hair keratin**type I hair keratin 1, **type I hair keratin 2, **type I hair keratin 3A, **type I hair keratin 3B, **type I hair keratin 4,...
s), which make up hairHairHair is a filamentous biomaterial, that grows from follicles found in the dermis. Found exclusively in mammals, hair is one of the defining characteristics of the mammalian class....
, nailsNail (anatomy)A nail is a horn-like envelope covering the dorsal aspect of the terminal phalanges of fingers and toes in humans, most non-human primates, and a few other mammals. Nails are similar to claws, which are found on numerous other animals....
, hornsHorn (anatomy)A horn is a pointed projection of the skin on the head of various animals, consisting of a covering of horn surrounding a core of living bone. True horns are found mainly among the ruminant artiodactyls, in the families Antilocapridae and Bovidae...
and reptilianReptileReptiles are members of a class of air-breathing, ectothermic vertebrates which are characterized by laying shelled eggs , and having skin covered in scales and/or scutes. They are tetrapods, either having four limbs or being descended from four-limbed ancestors...
scalesScale (zoology)In most biological nomenclature, a scale is a small rigid plate that grows out of an animal's skin to provide protection. In lepidopteran species, scales are plates on the surface of the insect wing, and provide coloration...
.
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.
Type III
There are four proteins classed as type III IF proteins, which may form homo- or heteropolymerHeteropolymer
A heteropolymer or copolymer is a polymer derived from two monomeric species, as opposed to a homopolymer where only one monomer is used...
ic proteins.
- DesminDesminDesmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
IFs are structural components of the sarcomereSarcomereA sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
s in muscle cells. - GFAPGlial fibrillary acidic proteinGlial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
(glial fibrillary acidic protein) is found in astrocyteAstrocyteAstrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s and other glia. - PeripherinPeripherinPeripherin is a protein that in humans is encoded by the PRPH gene.Peripherin is a type III Intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such...
found in peripheral neurons. - VimentinVimentinVimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, the most widely distributed of all IF proteins, can be found in fibroblastFibroblastA fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s, leukocytes, and blood vessel endothelial cells. They support the cellular membranes and keep some organelleOrganelleIn cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s in a fixed place within the cytoplasmCytoplasmThe cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
.
Type IV
- α-InternexinInternexinInternexin, alpha-internexin, is a Class IV intermediate filament approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord. The protein copurifies with other neurofilament subunits, as it was originally discovered, however in some mature neurons it can be the...
- NeurofilamentNeurofilamentNeurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
s - the type IV family of intermediate filaments that is found in high concentrations along the axonAxonAn axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s of vertebrate neurons. - SyneminSyneminSynemin, also called desmuslin, is an intermediate filament and, like other IFs, primarily functions to integrate mechanical stress and maintain structural integrity in eukaryotic cells. While it has been observed in a variety of cell types, it has been best studied in the sarcomere of skeletal...
- SyncoilinSyncoilinSyncoilin is a muscle-specific intermediate filament, first isolated as a binding partner to α-dystrobrevin, as determined by a yeast two-hybrid assay.Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of desmin...
Type V - Nuclear Lamins
- LaminLaminNuclear lamins, also known as Class V intermediate filaments, are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope...
s
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, B1 and B2, are expressed from the LMNB1 and LMNB2 genes on 5q23 and 19q13, respectively.
A-type lamins are only expressed following gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
. 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.
Cell adhesion
At the plasma membrane, some keratins interact with desmosomeDesmosome
A desmosome , also known as macula adherens , is a cell structure specialized for cell-to-cell adhesion...
s (cell-cell adhesion) and hemidesmosome
Hemidesmosome
Hemidesmosomes are very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. They are similar in form to desmosomes when visualized by electron microscopy. While desmosomes link two cells together, hemidesmosomes attach one cell to the...
s (cell-matrix adhesion) via adapter proteins.
Associated proteins
FilaggrinFilaggrin
Filaggrin is a filament-associated protein that binds to keratin fibers in epithelial cells.-Profilaggrin:Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of...
binds to keratin fibers in epidermal cells. Plectin
Plectin
Plectin is a giant protein found in nearly all mammalian cells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments. In addition plectin links the cytoskeleton to junctions found in the plasma membrane that...
links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
II.
Keratin filaments in epithelial cells link to desmosome
Desmosome
A desmosome , also known as macula adherens , is a cell structure specialized for cell-to-cell adhesion...
s (desmosomes connect the cytoskeleton together) through plakoglobin
Plakoglobin
Junction plakoglobin, also known as gamma-catenin or JUP, is a protein that in humans is encoded by the JUP gene.- Function :...
, desmoplakin
Desmoplakin
Desmoplakin is a protein associated with desmosomes.Desmoplakin is a protein that in humans is encoded by the DSP gene. The C-terminus of desmoplakin binds with intermediate filaments. These are further sub divided to three homologous Plakin repeat domains . In the mid-region of desmoplakin, a...
, desmoglein
Desmoglein
The desmogleins are a family of cadherins consisting of proteins DSG1, DSG2, DSG3, and DSG4. They play a role in the formation of desmosomes that join cells to one another....
s, and desmocollin
Desmocollin
Desmocollin is a type of cadherin.Specifically, it can refer to one of the following human genes :* DSC1* DSC2* DSC3...
s; desmin
Desmin
Desmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
filaments are connected in a similar way in heart muscle cells.
Diseases arising from mutations in IF genes
- Epidermolysis bullosa simplexEpidermolysis bullosa simplexEpidermolysis bullosa simplex is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Blister formation of EBS occurs at the dermoepidermal junction. Sometimes EBS is called epidermolytic.-Subtypes:...
; K5 or K14 mutation - Laminopathies are a family of diseases caused by mutations in nuclear lamins and include Hutchinson Gilford Progeria Syndrome and various lipodystrophies and cardiomyopathies among others.
- Human Intermediate Filament Database(HIFD), a comprehensive database of human intermediate filament proteins, their associated variations and diseases.
External links
- http://www.interfil.org/browse_interfil.php