Skip to main content
Log in

How the projection domains of NF-L and α-internexin determine the conformations of NF-M and NF-H in neurofilaments

  • Original Paper
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

An Erratum to this article was published on 20 April 2010

Abstract

Making use of a numerical self-consistent field method and polymer brush concepts, we model the solvated corona of neurofilaments (NF) composed of projection domains (unstructured tails) of constituent proteins. Projections are modeled with amino acid resolution. We focus on the importance of the two shortest ones (α-internexin and NF-L) in regulating the conformations of the two longer ones (NF-M and NF-H) in an isolated NF. We take the wild-type NF with no α-internexin as the reference, for which the phosphorylation-induced translocation of M- and H-tails has been examined previously. We demonstrate that a subbrush of L-tails creates an electrostatic potential profile with an approximately parabolic shape. An experimentally relevant (2:1) ratio of L- to α-projections reduces the charge density of the L subbrush and shifts the translocation transition of the H-tails to slightly higher degrees of phosphorylation. Replacing all L-tails by α-projections destroys the substructure of the NF corona and this alters the NF response to the phosphorylation of long tails.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Bathe M, Rutledge GC, Grodzinsky AJ, Tidorz B (2005) A coarse-grained molecular model for glycosaminoglycans: application to chondroitin, chondroitin sulfate, and hyaluronic acid. Biophys J 88:3870–3887

    Article  CAS  PubMed  Google Scholar 

  • Brown HG, Hoh JH (1997) Entropic exclusion of neurofilament side arms: a mechanism for maintaining interfilament spacing. Biochemistry 36:15035–15040

    Article  CAS  PubMed  Google Scholar 

  • Beck R, Deek J, Jones JB, Safinya CR (2010) Gel expanded to gel condensed transition in neurofilament networks revealed by direct force measurements. Nat Mater 9:40–46

    Article  CAS  PubMed  Google Scholar 

  • Chang R, Kwak Y, Gebremichael Y (2009) Structural properties of neurofilament sidearms: sequence-based modeling of neurofilament architecture. J Mol Biol 391:648–660

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Nakata T, Zhang Z, Hirokawa N (2000) The C-terminal tail domain of neurofilament protein-H (NF-H) forms the crossbridges and regulates neurofilament bundle formation. J Cell Sci 113:3861–3869

    CAS  PubMed  Google Scholar 

  • Fleer GJ, Cohen Stuart MA, Scheutjens JMHM, Cosgrove T, Vincent B (1993) Polymers at interfaces. Chapman & Hill, London

    Google Scholar 

  • Fuchs E, Cleveland DW (1998) A structural scaffolding of intermediate filaments in health and disease. Science 279:514–519

    Article  CAS  PubMed  Google Scholar 

  • Garcia ML, Lobsiger CS, Shah SB, Deerinck TJ, Crum J, Young D, Ward CM, Crawford TO, Gotow T, Uchiyama Y, Ellisman MH, Calcutt NA, Cleveland D (2003) NF-M is an essential target for the myelin-directed “outside-in” signaling cascade that mediates radial axonal growth. J Cell Biol 163:1011–1020

    Google Scholar 

  • Gou JP, Gotow T, Janmey PA, Leterrier JF (1998) 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 36:371–387

    Article  CAS  PubMed  Google Scholar 

  • Herrmann H, Aebi U (2004) Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular scaffolds. Annu Rev Biochem 73:749–789

    Article  CAS  PubMed  Google Scholar 

  • Hisanaga S, Hirokawa N (1988) Structure of the peripheral domains revealed by low-angle rotary shadowing. J Mol Biol 202:297–305

    Article  CAS  PubMed  Google Scholar 

  • Hisanaga S-I, Hirokawa N (1990) Molecular architecture of the neurofilament. II. Reassembly process of neurofilament L protein in vitro. J Mol Biol 211:871–882

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann PN, Lasek RJ (1975) Slow component of axonal-transport—idenfification of major structural polypeptides of axon and their generality among mammalian neurons. J Cell Biol 66:351–366

    Article  Google Scholar 

  • Janmey PA, Leterrier J-F, Herrmann H. (2003) Assembly and structure of neurofilaments. Curr Opin Coll Int Sci 8:40–47

    Article  CAS  Google Scholar 

  • Jones JB, Safinya CR (2008) Interplay between liquid crystalline and isotropic gels in self-assembled neurofilament networks. Biophys J 95:723–835

    Google Scholar 

  • Kumar S, Yin X, Trapp BD, Hoh JH, Paulatis ME (2002) Relating interactions between neurofilaments to the structure of axonal neurofilament distribution through polymer brush models. Biophys J 82:2360–2372

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Hoh JH (2004) Modulation of repulsive forces between neurofilaments by sidearm phosphorylation. Biochem Biophys Res Comm 324:489–496

    Article  CAS  PubMed  Google Scholar 

  • Lee MK, Xu ZS, Wong PC, Cleveland DW (1993) Neurofilaments are obligate heteropolyemrs in-vivo. J Cell Biol 122:1337–1350

    Article  CAS  PubMed  Google Scholar 

  • Leermakers FAM, Zhulina EB (2008) Self-consistent field modeling of the neurofilament network. Biophys Rev Lett 3:459–489

    Article  CAS  Google Scholar 

  • Liem RKH, Yen SH, Solomon GD, Shelanski ML (1978) Intermediate filaments in nervous tissues. J Cell Biol 79:637–645

    Article  CAS  PubMed  Google Scholar 

  • Luchko T, Huzil JT, Stepanova M, Tuszynski J (2008) Conformational analysis of the carboxy-terminal tails of human beta-tubulin isotypes. Biophys J 94:1971–1982

    Article  CAS  PubMed  Google Scholar 

  • Mitsutake A, Sugita Y, Okamoto Y (2001) Generalized-ensemble algorithms for molecular simulations of biopolymers. Biopolymers 60:96–123

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay R, Kumar S, Hoh JH (2004) Molecular mechanisms for organizing the neuronal cytoskeleton. BioEssays 26:1–9

    Article  Google Scholar 

  • Mulligan L, Balin BJ, Lee VMY, Ip W (1991) Antibody labeling of bovine neurofilaments: implications on the structure of neurofilament sidearms. J Struct Biol 166:145–160

    Article  Google Scholar 

  • Nap RJ, Szleifer I (2008) Structure and interactions of aggrecans: statistical thermodynamic approach. Biophys J 95:4570–4583

    Article  CAS  PubMed  Google Scholar 

  • Qu LJ, Jin XG, Liao Q (2009) Numerical self-consistent field theory of cylindrical polyelectrolyte brushes. Macromol Theory Simul 18:162–170

    Article  CAS  Google Scholar 

  • Rao MV, Garcia ML, Miyazaki Y, Gotow T, Yuan A, Mattina S, Ward CM, Calcutt NA, Uchiyama Y, Nixon RA, Cleveland D (2002) Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport. J Cell Biol 158:681–693

    Article  CAS  PubMed  Google Scholar 

  • Skvortsov AM, Klushin LI, Gorbunov AA (1997) Long and short chains in a polymeric brush: a conformational transition. Macromolecules 30:1818–1827

    Article  CAS  Google Scholar 

  • Skvortsov AM, Klushin LI, Leermakers FAM (2002) Exactly solved polymer models with conformational escape transitions of a coil-to-flower type. Europhys Lett 58:292–298

    Article  CAS  Google Scholar 

  • Sorin EJ, Pande VS (2005) Exploring the helix-coil transition via all-atom equilibrium ensemble simulations. Biophys J 88:2472–2493

    Article  CAS  PubMed  Google Scholar 

  • Stettler DD, Yamahachi H, Li W, Denk W, Gilbert CD (2006) Axons and synaptic boutons are highly dynamic in adult visual cortex. Neuron 49:877–887

    Article  CAS  PubMed  Google Scholar 

  • Yuan AD, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna, Liem RKH, Eyer J, Peterson AC, Julien J-P, Nixon RA (2006) α-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci 26:10006–10019

    Article  CAS  PubMed  Google Scholar 

  • Zhulina EB, Klein Wolterink J, Borisov OV (2000) Screening effects in polyelectrolyte brush: self-consistent field theory. Macromolecules 33:4945–4953

    Article  CAS  Google Scholar 

  • Zhulina EB, Leermakers FAM (2007) A self-consistent field analysis of the neurofilament brush with amino-acid resolution. Biophys J 93:1431–1441

    Article  Google Scholar 

  • Zhulina EB, Leermakers FAM (2007) Effect of the ionic strength and pH on the equilibrium structure of neurofilament brush. Biophys J 93:1452–1463

    Article  CAS  PubMed  Google Scholar 

  • Zhulina EB, Leermakers FAM (2010) The polymer brush model of neurofilament projections. Effect of protein composition. Biophys J 98:462–469

    Google Scholar 

Download references

Acknowledgments

The authors acknowledge financial support from the Dutch National Science Foundation (NWO) and the Russian Foundation for Basic Research (RFBR) through a joint project 047.017.026 “Polymers in nanomedicine: design, synthesis and study of inter-polymer and polymer-virus complexes in search of novel pharmaceutical strategies”. E.B.Z. acknowledges partial support from the Russian Foundation for Basic Research (RFBR grant 08-03-00336).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. A. M. Leermakers.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00249-010-0605-z

An erratum to this article is available at http://dx.doi.org/10.1007/s00249-010-0605-z.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leermakers, F.A.M., Zhulina, E.B. How the projection domains of NF-L and α-internexin determine the conformations of NF-M and NF-H in neurofilaments. Eur Biophys J 39, 1323–1334 (2010). https://doi.org/10.1007/s00249-010-0585-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-010-0585-z

Keywords

Navigation