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. 2002 May;82(5):2360–2372. doi: 10.1016/S0006-3495(02)75581-1

Relating interactions between neurofilaments to the structure of axonal neurofilament distributions through polymer brush models.

Sanjay Kumar 1, Xinghua Yin 1, Bruce D Trapp 1, Jan H Hoh 1, Michael E Paulaitis 1
PMCID: PMC1302028  PMID: 11964226

Abstract

Neurofilaments (NFs) have been proposed to interact with one another through mutual steric exclusion of their unstructured C-terminal "sidearm" domains, producing order in axonal NF distributions and conferring mechanical strength to the axon. Here we apply theory developed for polymer brushes to examine the relationship between the brush properties of the sidearms and NF organization in axons. We first measure NF-NF radial distribution functions and occupancy probability distributions for adult mice. Interpreting the probability distributions using information theory, we show that the NF distributions may be represented by a single pair potential of mean force. Then, to explore the relationship between model parameters and NF architecture, we conduct two-dimensional Monte Carlo simulations of NF cross-sectional distributions. We impose purely repulsive interaction potentials in which the sidearms are represented as neutral and polyelectrolyte chains. By treating the NFs as telechelic polymer brushes, we also incorporate cross-bridging interactions. Both repulsive potentials are capable of reproducing NF cross-sectional densities and their pair correlations. We find that NF structure is sensitive to changes in brush thickness mediated by chain charge, consistent with the experimental observation that sidearm phosphorylation regulates interfilament spacing. The presence of attractive cross-bridging interactions contributes only modestly to structure for moderate degrees of cross-bridging and leads to NF aggregation for extensive cross-bridging.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Braun J., Abney J. R., Owicki J. C. How a gap junction maintains its structure. 1984 Jul 26-Aug 1Nature. 310(5975):316–318. doi: 10.1038/310316a0. [DOI] [PubMed] [Google Scholar]
  2. Braun J., Abney J. R., Owicki J. C. Lateral interactions among membrane proteins. Valid estimates based on freeze-fracture electron microscopy. Biophys J. 1987 Sep;52(3):427–439. doi: 10.1016/S0006-3495(87)83232-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown H. G., Hoh J. H. Entropic exclusion by neurofilament sidearms: a mechanism for maintaining interfilament spacing. Biochemistry. 1997 Dec 9;36(49):15035–15040. doi: 10.1021/bi9721748. [DOI] [PubMed] [Google Scholar]
  4. Cassarino D. S., Bennett J. P., Jr An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev. 1999 Jan;29(1):1–25. doi: 10.1016/s0165-0173(98)00046-0. [DOI] [PubMed] [Google Scholar]
  5. Chen J., Nakata T., Zhang Z., Hirokawa N. The C-terminal tail domain of neurofilament protein-H (NF-H) forms the crossbridges and regulates neurofilament bundle formation. J Cell Sci. 2000 Nov;113(Pt 21):3861–3869. doi: 10.1242/jcs.113.21.3861. [DOI] [PubMed] [Google Scholar]
  6. Chin T. K., Eagles P. A., Maggs A. The proteolytic digestion of ox neurofilaments with trypsin and alpha-chymotrypsin. Biochem J. 1983 Nov 1;215(2):239–252. doi: 10.1042/bj2150239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chin T. K., Harding S. E., Eagles P. A. Characterization of two proteolytically derived soluble polypeptides from the neurofilament triplet components NFM and NFH. Biochem J. 1989 Nov 15;264(1):53–60. doi: 10.1042/bj2640053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coulombe P. A., Bousquet O., Ma L., Yamada S., Wirtz D. The 'ins' and 'outs' of intermediate filament organization. Trends Cell Biol. 2000 Oct;10(10):420–428. doi: 10.1016/s0962-8924(00)01828-6. [DOI] [PubMed] [Google Scholar]
  9. Eyer J., Leterrier J. F. Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments in vitro. Biochem J. 1988 Jun 15;252(3):655–660. doi: 10.1042/bj2520655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Geisler N., Weber K. Self-assembly in Vitro of the 68,000 molecular weight component of the mammalian neurofilament triplet proteins into intermediate-sized filaments. J Mol Biol. 1981 Sep 25;151(3):565–571. doi: 10.1016/0022-2836(81)90011-5. [DOI] [PubMed] [Google Scholar]
  11. Georges E., Mushynski W. E. Chemical modification of charged amino acid moieties alters the electrophoretic mobilities of neurofilament subunits on SDS/polyacrylamide gels. Eur J Biochem. 1987 Jun 1;165(2):281–287. doi: 10.1111/j.1432-1033.1987.tb11439.x. [DOI] [PubMed] [Google Scholar]
  12. Gotow T., Tanaka T., Nakamura Y., Takeda M. Dephosphorylation of the largest neurofilament subunit protein influences the structure of crossbridges in reassembled neurofilaments. J Cell Sci. 1994 Jul;107(Pt 7):1949–1957. doi: 10.1242/jcs.107.7.1949. [DOI] [PubMed] [Google Scholar]
  13. 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. 1998 May;36(3):371–387. doi: 10.1007/BF02522486. [DOI] [PubMed] [Google Scholar]
  14. Hisanaga S., Hirokawa N. Structure of the peripheral domains of neurofilaments revealed by low angle rotary shadowing. J Mol Biol. 1988 Jul 20;202(2):297–305. doi: 10.1016/0022-2836(88)90459-7. [DOI] [PubMed] [Google Scholar]
  15. Hoh J. H. Functional protein domains from the thermally driven motion of polypeptide chains: a proposal. Proteins. 1998 Aug 1;32(2):223–228. [PubMed] [Google Scholar]
  16. Hsieh S. T., Crawford T. O., Griffin J. W. Neurofilament distribution and organization in the myelinated axons of the peripheral nervous system. Brain Res. 1994 Apr 11;642(1-2):316–326. doi: 10.1016/0006-8993(94)90937-7. [DOI] [PubMed] [Google Scholar]
  17. Hummer G., Garde S., García A. E., Pohorille A., Pratt L. R. An information theory model of hydrophobic interactions. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8951–8955. doi: 10.1073/pnas.93.17.8951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jaffe H., Sharma P., Grant P., Pant H. Characterization of the phosphorylation sites of the squid (Loligo pealei) high-molecular-weight neurofilament protein from giant axon axoplasm. J Neurochem. 2001 Feb;76(4):1022–1031. doi: 10.1046/j.1471-4159.2001.00115.x. [DOI] [PubMed] [Google Scholar]
  19. Julien J. P. Neurofilament functions in health and disease. Curr Opin Neurobiol. 1999 Oct;9(5):554–560. doi: 10.1016/S0959-4388(99)00004-5. [DOI] [PubMed] [Google Scholar]
  20. Kramer E. M., Herzfeld J. Avoidance model for soft particles. II. Positional ordering of charged rods. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 2000 Jun;61(6 Pt B):6872–6878. doi: 10.1103/physreve.61.6872. [DOI] [PubMed] [Google Scholar]
  21. Leapman R. D., Gallant P. E., Reese T. S., Andrews S. B. Phosphorylation and subunit organization of axonal neurofilaments determined by scanning transmission electron microscopy. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7820–7824. doi: 10.1073/pnas.94.15.7820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lee M. K., Cleveland D. W. Neuronal intermediate filaments. Annu Rev Neurosci. 1996;19:187–217. doi: 10.1146/annurev.ne.19.030196.001155. [DOI] [PubMed] [Google Scholar]
  23. Lee V. M., Otvos L., Jr, Carden M. J., Hollosi M., Dietzschold B., Lazzarini R. A. Identification of the major multiphosphorylation site in mammalian neurofilaments. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1998–2002. doi: 10.1073/pnas.85.6.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lees J. F., Shneidman P. S., Skuntz S. F., Carden M. J., Lazzarini R. A. The structure and organization of the human heavy neurofilament subunit (NF-H) and the gene encoding it. EMBO J. 1988 Jul;7(7):1947–1955. doi: 10.1002/j.1460-2075.1988.tb03032.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Leterrier J. F., Eyer J. Properties of highly viscous gels formed by neurofilaments in vitro. A possible consequence of a specific inter-filament cross-bridging. Biochem J. 1987 Jul 1;245(1):93–101. doi: 10.1042/bj2450093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Leterrier J. F., Langui D., Probst A., Ulrich J. A molecular mechanism for the induction of neurofilament bundling by aluminum ions. J Neurochem. 1992 Jun;58(6):2060–2070. doi: 10.1111/j.1471-4159.1992.tb10947.x. [DOI] [PubMed] [Google Scholar]
  27. Leung C. L., Sun D., Liem R. K. The intermediate filament protein peripherin is the specific interaction partner of mouse BPAG1-n (dystonin) in neurons. J Cell Biol. 1999 Feb 8;144(3):435–446. doi: 10.1083/jcb.144.3.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McHale M. K., Hall G. F., Cohen M. J. Early cytoskeletal changes following injury of giant spinal axons in the lamprey. J Comp Neurol. 1995 Feb 27;353(1):25–37. doi: 10.1002/cne.903530105. [DOI] [PubMed] [Google Scholar]
  29. Mukhopadhyay R., Hoh J. H. AFM force measurements on microtubule-associated proteins: the projection domain exerts a long-range repulsive force. FEBS Lett. 2001 Sep 21;505(3):374–378. doi: 10.1016/s0014-5793(01)02844-7. [DOI] [PubMed] [Google Scholar]
  30. Mullins R. D., Kelleher J. F., Xu J., Pollard T. D. Arp2/3 complex from Acanthamoeba binds profilin and cross-links actin filaments. Mol Biol Cell. 1998 Apr;9(4):841–852. doi: 10.1091/mbc.9.4.841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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. 1994 Aug;126(4):1031–1046. doi: 10.1083/jcb.126.4.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pearson L. T., Chan S. I., Lewis B. A., Engelman D. M. Pair distribution functions of bacteriorhodopsin and rhodopsin in model bilayers. Biophys J. 1983 Aug;43(2):167–174. doi: 10.1016/S0006-3495(83)84337-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Perelson A. S. Spatial distribution of surface immunoglobulin on B lymphocytes. Local ordering. Exp Cell Res. 1978 Mar 15;112(2):309–321. doi: 10.1016/0014-4827(78)90214-8. [DOI] [PubMed] [Google Scholar]
  34. Povlishock J. T., Christman C. W. The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts. J Neurotrauma. 1995 Aug;12(4):555–564. doi: 10.1089/neu.1995.12.555. [DOI] [PubMed] [Google Scholar]
  35. Romero P., Obradovic Z., Kissinger C. R., Villafranca J. E., Garner E., Guilliot S., Dunker A. K. Thousands of proteins likely to have long disordered regions. Pac Symp Biocomput. 1998:437–448. [PubMed] [Google Scholar]
  36. Romero P., Obradovic Z., Li X., Garner E. C., Brown C. J., Dunker A. K. Sequence complexity of disordered protein. Proteins. 2001 Jan 1;42(1):38–48. doi: 10.1002/1097-0134(20010101)42:1<38::aid-prot50>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  37. Rost B., Sander C. Combining evolutionary information and neural networks to predict protein secondary structure. Proteins. 1994 May;19(1):55–72. doi: 10.1002/prot.340190108. [DOI] [PubMed] [Google Scholar]
  38. Rost B., Sander C. Prediction of protein secondary structure at better than 70% accuracy. J Mol Biol. 1993 Jul 20;232(2):584–599. doi: 10.1006/jmbi.1993.1413. [DOI] [PubMed] [Google Scholar]
  39. Rout M. P., Aitchison J. D., Suprapto A., Hjertaas K., Zhao Y., Chait B. T. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol. 2000 Feb 21;148(4):635–651. doi: 10.1083/jcb.148.4.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Smith D. H., Wolf J. A., Lusardi T. A., Lee V. M., Meaney D. F. High tolerance and delayed elastic response of cultured axons to dynamic stretch injury. J Neurosci. 1999 Jun 1;19(11):4263–4269. doi: 10.1523/JNEUROSCI.19-11-04263.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Strong M. J., Strong W. L., Jaffe H., Traggert B., Sopper M. M., Pant H. C. Phosphorylation state of the native high-molecular-weight neurofilament subunit protein from cervical spinal cord in sporadic amyotrophic lateral sclerosis. J Neurochem. 2001 Mar;76(5):1315–1325. doi: 10.1046/j.1471-4159.2001.00094.x. [DOI] [PubMed] [Google Scholar]
  42. Uversky V. N., Gillespie J. R., Fink A. L. Why are "natively unfolded" proteins unstructured under physiologic conditions? Proteins. 2000 Nov 15;41(3):415–427. doi: 10.1002/1097-0134(20001115)41:3<415::aid-prot130>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  43. Willard M., Simon C. Antibody decoration of neurofilaments. J Cell Biol. 1981 May;89(2):198–205. doi: 10.1083/jcb.89.2.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wootton J. C., Federhen S. Analysis of compositionally biased regions in sequence databases. Methods Enzymol. 1996;266:554–571. doi: 10.1016/s0076-6879(96)66035-2. [DOI] [PubMed] [Google Scholar]
  45. Yang Y., Dowling J., Yu Q. C., Kouklis P., Cleveland D. W., Fuchs E. An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments. Cell. 1996 Aug 23;86(4):655–665. doi: 10.1016/s0092-8674(00)80138-5. [DOI] [PubMed] [Google Scholar]
  46. Yin X., Crawford T. O., Griffin J. W., Tu P. h., Lee V. M., Li C., Roder J., Trapp B. D. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci. 1998 Mar 15;18(6):1953–1962. doi: 10.1523/JNEUROSCI.18-06-01953.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. de Waegh S. M., Lee V. M., Brady S. T. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell. 1992 Feb 7;68(3):451–463. doi: 10.1016/0092-8674(92)90183-d. [DOI] [PubMed] [Google Scholar]

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