Neurofilament Protein Heterotetramers as Assembly Intermediates

Cohlberg, Jeffrey A.; Hajarian, Hamid; Tran, Tan; Alipourjeddi, Parvaneh; Noveen, Alexander

doi:10.1074/jbc.270.16.9334

Cited by 66 publications

(44 citation statements)

References 45 publications

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“…N eurofilaments (NFs) are type IV intermediate filaments [1][2][3][4] unique to neuronal cells, where their physiologically relevant state in axons is a space-filling nematic liquidcrystal (LC) hydrogel (with parallel filament orientation) stabilizing the axonal calibre and protecting against mechanical stress 1,[5][6][7] . The NF network, which acts as a scaffold for microtubules, must be sufficiently flexible to allow for the transport of relatively large organelles (typically larger than the interfilament spacings) trafficking along microtubules immersed within the network [8][9][10][11] .…”

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Neurofilament sidearms modulate parallel and crossed-filament orientations inducing nematic to isotropic and re-entrant birefringent hydrogels

et al. 2013

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Neurofilaments are intermediate filaments assembled from the subunits neurofilament-low, neurofilament-medium and neurofilament-high. In axons, parallel neurofilaments form a nematic liquid-crystal hydrogel with network structure arising from interactions between the neurofilaments' C-terminal sidearms. Here we report, using small-angle X-ray-scattering, polarized-microscopy and rheometry, that with decreasing ionic strength, neurofilament-lowhigh, neurofilament-low-medium and neurofilament-low-medium-high hydrogels transition from the nematic hydrogel to an isotropic hydrogel (with random, crossed-filament orientation) and to an unexpected new re-entrant liquid-crystal hydrogel with parallel filaments-the bluish-opaque hydrogel-with notable mechanical and water retention properties reminiscent of crosslinked hydrogels. Significantly, the isotropic gel phase stability is sidearm-dependent: neurofilament-low-high hydrogels exhibit a wide ionic strength range, neurofilament-low-medium hydrogels a narrow ionic strength range, whereas neurofilamentlow hydrogels lack the isotropic gel phase. This suggests a dominant regulatory role for neurofilament-high sidearms in filament reorientation plasticity, facilitating organelle transport in axons. Neurofilament-inspired biomimetic hydrogels should therefore exhibit remarkable structure-dependent moduli and slow and fast water-release properties.

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“…1a) [1][2][3][4] . The NF subunits form the coiled-coil dimers neurofilamentlow-low (NF-LL), neurofilament-low-medium (NF-LM) and neurofilament-low-high (NF-LH) stabilized by the alpha-helical cores, which further assemble to form the flexible, 10 nm diameter NF filament with radially protruding unstructured C-terminal sidearms (Fig.…”

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Neurofilament sidearms modulate parallel and crossed-filament orientations inducing nematic to isotropic and re-entrant birefringent hydrogels

et al. 2013

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“…However, certain molecular details of these changes in IF composition remain unclear. It has not been determined yet whether type III vimentin or peripherin and type IV ␣-internexin copolymerize into the same IF and, if so, at which level of IF hierarchy: does this occur at the dimer (that is homo-versus heterodimer) or tetramer (that is different pairs of homodimers) (4,(42)(43)(44), or higher (45)?…”

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Molecular Parameters of Type IV α-Internexin and Type IV-Type III α-Internexin-Vimentin Copolymer Intermediate Filaments

Steinert

Marekov

Parry

1999

Journal of Biological Chemistry

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During neuronal development, a dynamic replacement mechanism occurs in which the type VI nestin and type III vimentin intermediate filament proteins are replaced by a series of type IV proteins beginning with ␣-internexin. We have explored molecular details of how the type III to type IV replacement process may occur. First, we have demonstrated by cross-linking experiments that bacterially expressed forms of ␣-internexin and vimentin form heterodimer molecules in vitro that assemble into copolymer intermediate filaments. We show using a urea disassembly assay that ␣-internexin molecules are likely to be more stable than those of vimentin. Second, by analyses of the induced cross-links, we have determined the axial lengths of ␣-internexin homodimer and ␣-internexin-vimentin heterodimer molecules and their modes of alignments in filaments. We report that these dimensions are the same as those reported earlier for vimentin homopolymer molecules and, by implication, are also the same for the other neuronal type IV proteins. These data suggest that during neuronal development, ␣-internexin molecules are readily assimilated onto the pre-existing vimentin cytoskeletal intermediate filament network because the axial lengths and axial alignments of their molecules are the same. Furthermore, the dynamic replacement process may be driven by a positive equilibrium due to the increased stability of the ␣-internexin network.

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“…Consequently, NF-L is more abundant than the other two subunits in neurons. NF-L is capable of homologous assembly, whereas NF-M and NF-H are not competent to assemble in the absence of NF-L (Cohlberg et al, 1995). Each neurofilament subunit consists of conserved head and rod domains and a more variable acidic tail domain.…”

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Superoxide Dismutase Catalyzes Nitration of Tyrosines by Peroxynitrite in the Rod and Head Domains of Neurofilament‐L

Crow

Ye²,

Strong

et al. 1997

Journal of Neurochemistry

236

123

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Superoxide dismutase (SOD) catalyzes the nitration of specific tyrosine residues in proteins by peroxynitrite (ONOO), which may be the damaging gain-offunction resulting from mutations to SOD associated with familial amyotrophic lateral sclerosis (ALS). We found that disassembled neurofilament-L (light subunit) was more susceptible to tyrosine nitration catalyzed by SOD in vitro. Neurofilament-L was selectively nitrated compared with the majority of other proteins present in brain homogenates. Assembled neurofilament-L was more resistant to nitration, suggesting that the susceptible tyrosine residues were protected by intersubunit contacts in assembled neurofilaments. Electrospray mass spectrometry of trypsin-digested neurofilament-L showed that tyrosine 17 in the head region and tyrosines 138, 177, and 265 in a-helical coil regions of the rod domain of neurofilament-L were particularly susceptible to SOD-catalyzed nitration. Nitrated neurofilament-L inhibited the assembly of unmodified neurofilament subunits, suggesting that the affected tyrosines are located in regions important for intersubunit contacts. Neurofilaments are major structural proteins expressed in motor neurons and known to be important for their survival in vivo. We suggest that SODcatalyzed nitration of neurofilament-L may have a significant role in the pathogenesis of ALS.

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Neurofilament Protein Heterotetramers as Assembly Intermediates

Cited by 66 publications

References 45 publications

Neurofilament sidearms modulate parallel and crossed-filament orientations inducing nematic to isotropic and re-entrant birefringent hydrogels

Neurofilament sidearms modulate parallel and crossed-filament orientations inducing nematic to isotropic and re-entrant birefringent hydrogels

Molecular Parameters of Type IV α-Internexin and Type IV-Type III α-Internexin-Vimentin Copolymer Intermediate Filaments

Superoxide Dismutase Catalyzes Nitration of Tyrosines by Peroxynitrite in the Rod and Head Domains of Neurofilament‐L

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