Name = Internexin neuronal intermediate filament protein, alpha
HGNCid = 6057
Symbol = INA
AltSymbols = NEF5
EntrezGene = 9118
OMIM = 605338
RefSeq = NM_032727
UniProt = Q5SYD2
Chromosome = 10
Arm = q
Band = 24
Internexin, alpha-internexin, is a Class IV
intermediate filamentapproximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord Levavasseur F, Zhu Q, and JP Julien. No requirement of alpha-internexin for nervous system development and for radial growth of axons. Molecular Brain Research. 69:104-112. (1999).] . The protein copurifies with other neurofilamentsubunits, as it was originally discovered, however in some mature neurons it can be the only neurofilament expressed. The protein is present in developing neuroblastsand in the Central Nervous Systemof adults. The protein is a major component of the intermediate filament network in small interneuronsand cerebellar granule cells, where it is present in the parallel fibers.
Alpha-internexin has a homologous central
rod domainof approximately 310 amino acidresidues 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. [Lariviere, R. and JP Julien. Functions of Intermediate Filaments in Neuronal Development and Disease. Journal of Neurobiology. 58(1): 131-48. (2004).] This rod domain is also involved in the 10nm 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 serineand threoninepolymers while the tail region has distinct sequence motifs like a glutamate rich region. [http://www.encorbio.com/cpolyclonal/CPCA-int.htm Catalogue# CPCA--Int: Chicken Polyclonal Antibody to alpha-internexin. Encor Biotechnology Inc. 2006.] ] The alpha domain is composed of heptadrepeats of hydrophobic residues that aid the formation of a coiled coilstructure. The structure of Alpha-internexin is highly conserved between rats, mice and humans.
Alpha-internexin can form homopolymers, unlike the
heteropolymerthe neurofilamentsform. 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 filament polypeptideschains form a dimervia their a-helical rod domains; these dimers can be either homodimers or heterodimers.
*Step 2: the dimers may associate laterally to form antiparallel, unstaggered
tetramersor 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
longitudinalassociations lead to the formation of protofibrils (octamers) and ultimately 10 nm intermediate filaments. [Ching G and R. Liem. Analysis of roles of the head domains of type IV rat neuronal intermediate filament proteins in filament assembly using domain-swapped chimeric proteins. Journal of Cell Science. 112:2233-2240. (1999).]
The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins.Duprey, P and D. Paulin. What can be learned from intermediate filament gene regulation in the mouse embryo? International Journal of Developmental Biology. 39:443-457. (1995).] 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
peripherin. As development continues into neurons the neurofilamenttriplet 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 neuroblastphase 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 cytoplasmof 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 neuronal development and has been suggested to play a role in axonal outgrowth. Gefiltin and xefiltin, homologs of α-internexin in
zebrafishand Xenopus laevis, respectively, are highly expressed during retinal growth and opticaxon 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 systemwhich 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.
α-internexin has also been implicated in several degenerative diseases such as
Amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson’s Disease, neuropathies, tropical spastic paraparesisand 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.
* [http://www.ihop-net.org/UniPub/iHOP/gs/320717.html Interactions of internexin alpha]
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