Composite bottlebrush mechanics: α-internexin fine-tunes neurofilament network properties

Kornreich, Micha; Malka-Gibor, Eti; Laser-Azogui, Adi; Doron, Ofer; Herrmann, Harald; Beck, Roy

doi:10.1039/c5sm00662g

Cited by 31 publications

(59 citation statements)

References 48 publications

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“…6H). Similar chain interpenetration behavior has been reported for protruding neurofilament side arms, which are also unstructured polyampholytes, at high osmotic pressures (68)(69)(70).…”

Section: )]mentioning

confidence: 54%

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Chung

Choi

Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer's. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; Φ Tau = 1/ 10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to P B ∼ 10,000-20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (P B ∼ 1,000-2,000 Pa) over the same range. Remarkably, the abrupt increase in P B observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < Φ Tau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT-MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.Tau | intrinsically disordered proteins | microtubule | SAXS | force measurement

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“…6H). Similar chain interpenetration behavior has been reported for protruding neurofilament side arms, which are also unstructured polyampholytes, at high osmotic pressures (68)(69)(70).…”

Section: )]mentioning

confidence: 54%

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Chung

Choi

Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, it suggests that specific cross-linking is involved in the unusually short spacing observed between composite filaments composed of NF-M and NF-L proteins. A recent study, applying the same model to composite networks of a-Inx and the NF triplet, demonstrated a wider spacing is found between composite filaments composed of NF-M and a-Inx proteins [181]. This trend is opposite to the mean field expectation, as a-Inx is both shorter, less charged and more hydrophobic than NF-L, and therefore would not be expected to increase the inter-filament spacing [131].…”

Section: Tail-to-tail Inter-filament Attractive and Repulsive Interacmentioning

confidence: 96%

“…2C), in which the stretched grafted end forms the ''stem'' of the flower-like tip [129][130][131]. Alternatively, strong surface or adjacent polymer attractions may prevent the formation of the outer ''flower'' corona and will result with preferable collapsed configuration, termed ''truffle conformation'' [132] (Fig. 2D).…”

Section: Theoretical Modeling Of Polymer Brushesmentioning

confidence: 99%

Order and disorder in intermediate filament proteins

et al. 2015

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Edited by Wilhelm Just Keywords:Intermediate filament Intrinsically disordered protein Cytoskeleton Polymer brush Self-assembly a b s t r a c t Intermediate filaments (IFs), important components of the cytoskeleton, provide a versatile, tunable network of self-assembled proteins. IF proteins contain three distinct domains: an a-helical structured rod domain, flanked by intrinsically disordered head and tail domains. Recent studies demonstrated the functional importance of the disordered domains, which differ in length and amino-acid sequence among the 70 different human IF genes. Here, we investigate the biophysical properties of the disordered domains, and review recent findings on the interactions between them. Our analysis highlights key components governing IF functional roles in the cytoskeleton, where the intrinsically disordered domains dictate protein-protein interactions, supramolecular assembly, and macro-scale order.

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“…1982;LiemandHutchison 1982;JulienandMushynski 1983; Hirokawa et al 1984; Nakagawa et al 1995; Chen et al 2000; Rao et al 2002b, 2003). Finally, recent evidence indicates that α-internexin fine-tunes the NF network through increasing interfilament spacing (Kornreich et al 2015). …”

Section: Nf Protein Domain Structure and Assemblymentioning

confidence: 99%

Neurofilaments and Neurofilament Proteins in Health and Disease

Yuan

Rao

Veeranna

et al. 2017

Cold Spring Harb Perspect Biol

515

493

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SUMMARY Neurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L [neurofilament light]; NF-M [neurofilament middle];NF-H [neurofilament heavy];and α-internexin or peripherin), each having different domain structures and functions. Here, we review how NFs provide structural support for the highly asymmetric geometries of neurons and, especially, for the marked radial expansion of myelinated axons crucial for effective nerve conduction velocity. NFs in axons extensively cross-bridge and interconnect with other non-IF components of the cytoskeleton, including microtubules, actin filaments, and other fibrous cytoskeletal elements, to establish a regionally specialized network that undergoes exceptionally slow local turnover and serves as a docking platform to organize other organelles and proteins. We also discuss how a small pool of oligomeric and short filamentous precursors in the slow phase of axonal transport maintains this network. A complex pattern of phosphorylation and dephosphorylation events on each subunit modulates filament assembly, turnover, and organization within the axonal cytoskeleton. Multiple factors, and especially turnover rate, determine the size of the network, which can vary substantially along the axon. NF gene mutations cause several neuroaxonal disorders characterized by disrupted subunit assembly and NF aggregation. Additional NF alterations are associated with varied neuropsychiatric disorders. New evidence that subunits of NFs exist within postsynaptic terminal boutons and influence neurotransmission suggests how NF proteins might contribute to normal synaptic function and neuropsychiatric disease states.

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Composite bottlebrush mechanics: α-internexin fine-tunes neurofilament network properties

Cited by 31 publications

References 48 publications

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Order and disorder in intermediate filament proteins

Neurofilaments and Neurofilament Proteins in Health and Disease

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