Abstract
Neurofilaments are essential cytoskeletal filaments that impart mechanical stability to axons. They are mostly assembled from three neurofilament proteins that form the core of the filament and its sidearms. Adjacent neurofilaments interact with each other through their apposing sidearms and attain unique conformations depending on the ionic condition, phosphorylation state, and interfilament separations. To understand the conformational properties of apposing sidearms under various conditions and gain insight into interfilament interactions, we performed Monte Carlo simulations of neurofilament pairs. We employed a sequence-based coarse-grained model of apposing NF sidearms that are end-tethered to cylindrical geometries according to the stoichiometry of the three neurofilament subunits. Monte Carlo simulations were conducted under different conditions such as phosphorylation state, ionic condition, and interfilament separations. Under salt-free conditions, apposing sidearms are found to adopt mutually excluding stretched but bent away conformations that are reminiscent of a repulsive type of interaction. Under physiological conditions, apposing sidearms are found to be in a coiled conformation, suggesting a short-range steric repulsive type of interaction. Increased sidearm mutual interpenetration and a simultaneous decrease in the individual brush heights were observed as the interfilament separation was reduced from 60 to 40 nm. The observed conformations suggest entropic interaction as a likely mechanism for sidearm-mediated interfilament interactions under physiological conditions.
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References
Fuchs, E., Cleveland, D.W.: A structural scaffolding of intermediate filaments in health and disease. Science 279(5350), 514–519 (1998)
Lee, M.K., Cleveland, D.W.: Neuronal intermediate filaments. Annu. Rev. Neurosci. 19, 187–217 (1996)
Povlishock, J.T., Christman, C.W.: The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts. J. Neurotrauma 12(4), 555–564 (1995)
Steinert, P.R., Roop, D.R.: Molecular and cellular biology of intermediate filaments. Annu. Rev. Biochem. 57, 593–625 (1988)
Friede, R.L., Samorajski, T.: Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat. Rec. 167(4), 379–387 (1970)
Barry, D.M., Carpenter, C., Yager, C., Golik, B., Barry, K.J., Shen, H., Mikse, O., Eggert, L.S., Schulz, D.J., Garcia, M.L.: Variation of the neurofilament medium KSP repeat sub-domain across mammalian species: implications for altering axonal structure. J. Exp. Biol. 213(1), 128–136 (2010)
Perrot, R., Berges, R., Bocquet, A., Eyer, J.: Review of the multiple aspects of neurofilament functions, and their possible contribution to neurodegeneration. Mol. Neurobiol. 38(1), 27–65 (2008)
Delisle, M.B., Carpenter, S.: Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J. Neurol. Sci. 63(2), 241–250 (1984)
Munoz, D.G., Greene, C., Perl, D.P., Selkoe, D.J.: Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients. J. Neuropathol. Exp. Neurol. 47(1), 9–18 (1988)
Goldman, J.E., Yen, S.H., Chiu, F.C., Peress, N.S.: Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science 221(4615), 1082–1084 (1983)
Fabrizi, G.M., Cavallaro, T., Angiari, C., Cabrini, I., Taioli, F., Malerba, G., Bertolasi, L., Rizzuto, N.: Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain 130(Pt 2), 394–403 (2007)
Donaghy, M., King, R.H., Thomas, P.K., Workman, J.M.: Abnormalities of the axonal cytoskeleton in giant axonal neuropathy. J. Neurocytol. 17(2), 197–208 (1988)
Sternberger, N.H., Sternberger, L.A., Ulrich, J.: Aberrant neurofilament phosphorylation in Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 82(12), 4274–4276 (1985)
Ishii, T., Haga, S., Tokutake, S.: Presence of neurofilament protein in Alzheimer’s neurofibrillary tangles (ANT). An immunofluorescent study. Acta Neuropathol. 48(2), 105–112 (1979)
Geisler, N., Kaufmann, E., Fischer, S., Plessmann, U., Weber, K.: Neurofilament architecture combines structural principles of intermediate filaments with carboxy-terminal extensions increasing in size between triplet proteins. EMBO J. 2(8), 1295–1302 (1983)
Yuan, A., Rao, M.V., Sasaki, T., Chen, Y., Kumar, A., Veeranna, Liem, R.K., Eyer, J., Peterson, A.C., Julien, J.P., Nixon, R.A.: Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J. Neurosci. 26(39), 10006–10019 (2006)
Yuan, A., Sasaki, T., Kumar, A., Peterhoff, C.M., Rao, M.V., Liem, R.K., Julien, J.P., Nixon, R.A.: Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons. J. Neurosci. 32(25), 8501–8508 (2012)
Carpenter, D.A., Wallace, l.: Neurofilament triplet protein interactions: evidence for the preferred formation of NF-L-containing dimers and a putative function for the end domains. J. Cell Sci. 109(Pt 10), 2493–2498 (1996)
Janmey, P.A., Leterrier, J.F., Herrmann, H.: Assembly and structure of neurofilaments. Curr. Opin. Colloid Interface Sci. 8(1), 40–47 (2003)
Jacomy, H., Zhu, Q., Couillard-Despres, S., Beaulieu, J.M., Julien, J.P.: Disruption of type IV intermediate filament network in mice lacking the neurofilament medium and heavy subunits. J. Neurochem. 73(3), 972–984 (1999)
Carter, J., Gragerov, A., Konvicka, K., Elder, G., Weinstein, H., Lazzarini, R.A.: Neurofilament (NF) assembly; divergent characteristics of human and rodent NF-L subunits. J. Biol. Chem. 273(9), 5101–5108 (1998)
Heins, S., Wong, P.C., Muller, S., Goldie, K., Cleveland, D.W., Aebi, U.: The rod domain of NF-L determines neurofilament architecture, whereas the end domains specify filament assembly and network formation. J. Cell Biol. 123(6 Pt 1), 1517–1533 (1993)
Stevens, M.J., Hoh, J.H.: Interactions between planar grafted neurofilament side-arms. J. Phys. Chem., B 115(23), 7541–7549 (2011)
Zhulina, E.B., Leermakers, F.A.: A self-consistent field analysis of the neurofilament brush with amino-acid resolution. Biophys. J. 93(5), 1421–1430 (2007)
Chang, R., Kwak, Y., Gebremichael, Y.: Structural properties of neurofilament sidearms: sequence-based modeling of neurofilament architecture. J. Mol. Biol. 391(3), 648–660 (2009)
Qianqian Cao, C.Z., He, H., Li, L.: A molecular dynamics study of two apposing polyelectrolyte brushes with mono and multivalent counterions. Macromol. Theory Simul. 18, 441–452 (2009)
Korobko, A.V., Jesse, W., Egelhaaf, S.U., Lapp, A., van der Maarel, J.R.: Do spherical polyelectrolyte brushes interdigitate? Phys. Rev. Lett. 93(17), 177801 (2004)
Stevenson, W., Chang, R., Gebremichael, Y.: Phosphorylation-mediated conformational changes in the mouse neurofilament architecture: insight from a neurofilament brush model. J. Mol. Biol. 405(4), 1101–1118 (2011)
McQuarrie, D.A.: Statistical Mechanics. University Science Books, Sausalito, CA (2000)
Smit, B., Fenkel, D.: Understanding Molecular Simulation: From Algorithms to Applications, Computational Science Series, vol. 1, 2nd edn. Academic Press, San Diego, CA (2002)
Xu, Z., Marszalek, J.R., Lee, M.K., Wong, P.C., Folmer, J., Crawford, T.O., Hsieh, S.T., Griffin, J.W., Cleveland, D.W.: Subunit composition of neurofilaments specifies axonal diameter. J. Cell Biol. 133(5), 1061–1069 (1996)
Kumar, S., Hoh, J.H.: Modulation of repulsive forces between neurofilaments by sidearm phosphorylation. Biochem. Biophys. Res. Commun. 324(2), 489–496 (2004)
Hsieh, S.T., Crawford, T.O., Griffin, J.W.: Neurofilament distribution and organization in the myelinated axons of the peripheral nervous-system. Brain Res. 642(1–2), 316–326 (1994)
Martin, R., Door, R., Ziegler, A., Warchol, W., Hahn, J., Breitig, D.: Neurofilament phosphorylation and axon diameter in the squid giant fibre system. Neuroscience 88(1), 327–336 (1999)
Glicksman, M.A., Soppet, D., Willard, M.B.: Posttranslational modification of neurofilament polypeptides in rabbit retina. J. Neurobiol. 18(2), 167–196 (1987)
Nixon, R.A., Paskevich, P.A., Sihag, R.K., Thayer, C.Y.: Phosphorylation on carboxyl terminus domains of neurofilament proteins in retinal ganglion cell neurons in vivo: influences on regional neurofilament accumulation, interneurofilament spacing, and axon caliber. J. Cell Biol. 126(4), 1031–1046 (1994)
Hsieh, S.T., Kidd, G.J., Crawford, T.O., Xu, Z.S., Lin, W.M., Trapp, B.D., Cleveland, D.W., Griffin, J.W.: Regional modulation of neurofilament organization by myelination in normal axons. J. Neurosci. 14(11), 6392–6401 (1994)
Carden, M.J., Trojanowski, J.Q., Schlaepfer, W.W., Lee, V.M.: Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns. J. Neurosci. 7(11), 3489–3504 (1987)
Dewaegh, S.M., Lee, V.M.Y., Brady, S.T.: Local modulation of Neurofilament phosphorylation, axonal caliber, and slow axonal-transport by myelinating Schwann-cells. Cell 68(3), 451–463 (1992)
Panwar, A.S., Kumar, S.: Brownian dynamics simulations of polyelectrolyte adsorption in shear flow. J. Chem. Phys. 122(15), 154902 (2005)
Frishchknecht, A.L.: Forces between nanorods with end-adsorbed chains in a homopolymer melt. J. Chem. Phys. 128(22), 224902 (2008)
Wittemann, A., Drechsler, M., Talmon, Y., Ballauff, M.: High elongation of polyelectrolyte chains in the osmotic limit of spherical polyelectrolyte brushes: a study by cryogenic transmission electron microscopy. J. Am. Chem. Soc. 127(27), 9688–9689 (2005)
Carden, M.J., Trojanowski, J.Q., Schlaepfer, W.W., Lee, V.M.: Two-stage expression of neurofilament polypeptides during rat neurogenesis with early establishment of adult phosphorylation patterns. J. Neurosci. 7(11), 3489–3504 (1987)
Brown, H.G., Hoh, J.H.: Entropic exclusion by neurofilament sidearms: a mechanism for maintaining interfilament spacing. Biochemistry 36(49), 15035–15040 (1997)
Hirokawa, N., Glicksman, M.A., Willard, M.B.: Organization of mammalian neurofilament polypeptides within the neuronal cytoskeleton. J. Cell Biol. 98(4), 1523–1536 (1984)
Hirokawa, N.: Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J. Cell Biol. 94(1), 129–142 (1982)
Leterrier, J.F., Kas, J., Hartwig, J., Vegners, R., Janmey, P.A.: Mechanical effects of neurofilament cross-bridges—modulation by phosphorylation, lipids, and interactions with F-actin. J. Biol. Chem. 271(26), 15687–15694 (1996)
Letterier, J.F., Eyre, J.: Properties of highly viscous gels formed by neurofilament in vitro: a possible consequence of a specific inter-filament cross-bridging. Biochem. J. 245, 93–101 (1987)
Price, R.L., Paggi, P., Lasek, R.J., Katz, M.J.: Neurofilaments are spaced randomly in the radial dimension of axons. J. Neurocytol. 17(1), 55–62 (1988)
Mukhopadhyay, R., Kumar, S., Hoh, J.H.: Molecular mechanisms for organizing the neuronal cytoskeleton. BioEssays 26(9), 1017–1025 (2004)
Beck, R., Deek, J., Jones, J.B., Safinya, C.R.: Gel-expanded to gel-condensed transition in neurofilament networks revealed by direct force measurements. Nat. Mater. 9(1), 40–46 (2010)
Gou, J.P., Gotow, T., Janmey, P.A., Leterrier, J.F.: Regulation of neurofilament interactions in vitro by natural and synthetic polypeptides sharing Lys-Ser-Pro sequences with the heavy neurofilament subunit NF-H: neurofilament crossbridging by antiparallel sidearm overlapping. Med. Biol. Eng. Comput. 36(3), 371–387 (1998)
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R.C. acknowledges support from the Korea Research Foundation (KRF) grant funded by the Korean government (MEST) (No. 2010–0003087) and the Kwangwoon Research Fund (2012) for this research.
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Jayanthi, L., Stevenson, W., Kwak, Y. et al. Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes. J Biol Phys 39, 343–362 (2013). https://doi.org/10.1007/s10867-012-9293-5
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DOI: https://doi.org/10.1007/s10867-012-9293-5