Internexin
Encyclopedia
Internexin, 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 only neurofilament expressed. The protein is present in developing neuroblasts and in the Central Nervous System
of adults. The protein is a major component of the intermediate filament network in small interneurons and cerebellar granule cells, where it is present in the parallel fibers.
central rod domain of approximately 310 amino acid
residues that form a highly conserved alpha helical region
. The central rod domain is responsible for coiled-coil structure and is flanked by an amino terminal head region and a carboxy terminal tail. This rod domain is also involved in the 10 nm filament assembly structure. The head and tail regions contain segments that are highly homologous to the NF-M’s structure. The head region is highly basic and contains many serine
and threonine
polymers while the tail region has distinct sequence motifs like a glutamate rich region. The alpha domain is composed of heptad repeats of hydrophobic
residue
s that aid the formation of a coiled coil
structure. The structure of Alpha-internexin is highly conserved between rats, mice and humans.
Alpha-internexin can form homopolymers
, unlike the heteropolymer
the neurofilaments form. This formation suggests that α-internexin and the three neurofilaments form separate filament systems. Not only can alpha-internexin form homopolymers but it form a network of extended filaments in the absence of other intermediate filament proteins and efficiently co-assemble with any type IV or type III subunit, in vitro. In Ching et al., a model of the intermediate filaments assembly is proposed. This model includes the following steps:
The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins. If one genetically deletes NF-M and/or NF-H in mice, the transport and presence, in the axons of the Central Nervous System, of α-internexin will be drastically reduced. Not only are they functionally similar, the turnover rates are also similar among the four proteins.
. As development continues into neurons the neurofilament
triplet proteins (NF-L: neurofilament low molecular mass
, NF-M: neurofilament medium molecular mass, and NF-H: neurofilament high molecular mass) are expressed in increasing molecular mass order as α-internexin expression decreases. In the neuroblast
phase of development α-internexin is found in the neural tube and neural crest derived neuroblasts.
In adult cells
, α-internexin is expressed abundantly in the central nervous system
, in the cytoplasm
of neurons, along with the neurofilament triplet proteins. They are expressed in a relatively fixed stoichiometric
ration to neurofilaments.
Alpha-internexin is a brain and central nervous system filament that is involved in neuron
al development and has been suggested to play a role in axon
al outgrowth. Gefiltin and xefiltin, homologs of α-internexin in zebrafish and Xenopus laevis, respectively, are highly expressed during retinal
growth and optic
axon regeneration and therefore have aided the speculation that α-internexin and axonal outgrowth may be connected. With this speculation, studies have been performed to develop a stronger bridge between the two. Through knockout studies using mice, the inhibition of α-internexin had no visible effect on development of the nervous system
which suggests that axonal outgrowth is unaffected by α-internexin, however, the knockout study failed to rule out subtle differences that the protein may have caused. Not only has α-internexin been linked to axonal outgrowth but it may regulate axonal stability or diameter through changes in filaments
and their subunit
composition. Also, internexin could be involved in the maintenance or the formation of dendritic spines. There have been many implications as to the function of α-internexin, however, there has been no concrete evidence to neither fully accept nor negate these speculations.
, dementia with Lewy bodies
, Parkinson’s Disease, neuropathies, tropical spastic paraparesis
and HTLV-1 associated myelopathy. In HTLV-1 myelopathy, Tax, transactivator expressed by HTLV-1, interacts with α-internexin in cell culture resulting in dramatic reduction in Tax transcactivation and intermediate filament formation.
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord. The protein copurifies
Copurification
Copurification in a chemical or biochemical context is the physical separation by chromatography or other purification technique of two or more substances of interest from other contaminating substances...
with other neurofilament
Neurofilament
Neurofilaments 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...
subunits, as it was originally discovered, however in some mature neurons it can be the only neurofilament expressed. The protein is present in developing neuroblasts and in the Central Nervous System
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
of adults. The protein is a major component of the intermediate filament network in small interneurons and cerebellar granule cells, where it is present in the parallel fibers.
Structure
Alpha-internexin has a homologousHomology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
central rod domain of approximately 310 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues that form a highly conserved alpha helical region
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The central rod domain is responsible for coiled-coil structure and is flanked by an amino terminal head region and a carboxy terminal tail. This rod domain is also involved in the 10 nm filament assembly structure. The head and tail regions contain segments that are highly homologous to the NF-M’s structure. The head region is highly basic and contains many serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
polymers while the tail region has distinct sequence motifs like a glutamate rich region. The alpha domain is composed of heptad repeats of hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
residue
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
s that aid the formation of 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...
structure. The structure of Alpha-internexin is highly conserved between rats, mice and humans.
Alpha-internexin can form homopolymers
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
, unlike the heteropolymer
Heteropolymer
A heteropolymer or copolymer is a polymer derived from two monomeric species, as opposed to a homopolymer where only one monomer is used...
the neurofilaments form. This formation suggests that α-internexin and the three neurofilaments form separate filament systems. Not only can alpha-internexin form homopolymers but it form a network of extended filaments in the absence of other intermediate filament proteins and efficiently co-assemble with any type IV or type III subunit, in vitro. In Ching et al., a model of the intermediate filaments assembly is proposed. This model includes the following steps:
- Step 1: in the first step of IF assembly two parallel, unstaggered intermediate filamentIntermediate filamentIntermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
polypeptides chains form a dimerProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
via their a-helicalAlpha helixA common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
rod domains; these dimers can be either homodimersProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
or heterodimerProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s. - Step 2: the dimers may associate laterally to form antiparallel, unstaggered tetramers or antiparallel, staggered tetramers.
- Step 3: the dimers may also associate longitudinally with a short head-to-tail overlap of the a-helical rod domains.
- Step 4: these lateral and longitudinal associations lead to the formation of protofibrils (octamers) and ultimately 10 nm intermediate filaments.
The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins. If one genetically deletes NF-M and/or NF-H in mice, the transport and presence, in the axons of the Central Nervous System, of α-internexin will be drastically reduced. Not only are they functionally similar, the turnover rates are also similar among the four proteins.
Function and Expression
It is expressed in early development in the neuroblast along with α-internexin and peripherinPeripherin
Peripherin 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...
. As development continues into neurons the neurofilament
Neurofilament
Neurofilaments 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...
triplet proteins (NF-L: neurofilament low molecular mass
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
, NF-M: neurofilament medium molecular mass, and NF-H: neurofilament high molecular mass) are expressed in increasing molecular mass order as α-internexin expression decreases. In the neuroblast
Neuroblast
A neuroblast is a dividing cell that will develop into neurons or glia. The characterisation of neuroblasts and their development in Drosophila melanogaster was widely achieved by Chris Doe, Corey Goodman and Mike Bate. In humans, neuroblasts produced by stem cells in the adult subventricular zone...
phase of development α-internexin is found in the neural tube and neural crest derived neuroblasts.
In adult cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, α-internexin is expressed abundantly in the central nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, in the 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...
of neurons, along with the neurofilament triplet proteins. They are expressed in a relatively fixed stoichiometric
Stoichiometry
Stoichiometry is a branch of chemistry that deals with the relative quantities of reactants and products in chemical reactions. In a balanced chemical reaction, the relations among quantities of reactants and products typically form a ratio of whole numbers...
ration to neurofilaments.
Alpha-internexin is a brain and central nervous system filament that is involved in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al development and has been suggested to play a role in axon
Axon
An 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....
al outgrowth. Gefiltin and xefiltin, homologs of α-internexin in zebrafish and Xenopus laevis, respectively, are highly expressed during retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
growth and optic
Optic
Optic may mean:* optic, a British term for a device for dispensing fixed amounts of alcoholic spirits* Optics, the study of the behavior and properties of light* An optical element or component, such as a lens, prism, or mirror...
axon regeneration and therefore have aided the speculation that α-internexin and axonal outgrowth may be connected. With this speculation, studies have been performed to develop a stronger bridge between the two. Through knockout studies using mice, the inhibition of α-internexin had no visible effect on development of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
which suggests that axonal outgrowth is unaffected by α-internexin, however, the knockout study failed to rule out subtle differences that the protein may have caused. Not only has α-internexin been linked to axonal outgrowth but it may regulate axonal stability or diameter through changes in filaments
Protein filament
In biology, a filament is a "long chain of proteins, such as those found in hair, muscle, or in flagella". They are often bundled together for strength and rigidity. Some cellular examples include:*Actin filaments*Microtubules*Intermediate filaments...
and their subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
composition. Also, internexin could be involved in the maintenance or the formation of dendritic spines. There have been many implications as to the function of α-internexin, however, there has been no concrete evidence to neither fully accept nor negate these speculations.
Disease Associations
α-internexin has also been implicated in several degenerative diseases such as Amyotrophic lateral sclerosisAmyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
, dementia with Lewy bodies
Dementia with Lewy bodies
Dementia with Lewy bodies , also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type, is a type of dementia closely allied to both Alzheimers and Parkinson's Diseases...
, Parkinson’s Disease, neuropathies, tropical spastic paraparesis
Tropical spastic paraparesis
Tropical spastic paraparesis , also known as HTLV-associated myelopathy or chronic progressive myelopathy, is an infection of the spinal cord by Human T-lymphotropic virus resulting in paraparesis, weakness of the legs...
and HTLV-1 associated myelopathy. In HTLV-1 myelopathy, Tax, transactivator expressed by HTLV-1, interacts with α-internexin in cell culture resulting in dramatic reduction in Tax transcactivation and intermediate filament formation.