Effect of neurodegenerative mutations in NEFL gene on thermal denaturation of the neurofilament light chain protein

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Abstract

The effects of amino acid substitutions E90K, N98S and A149V in the light chain of neurofilaments (NFL) on the structure and thermal denaturation of the NFL molecule was investigated. By using the circular dichroism spectroscopy, it was shown that these substitutions do not lead to a changes in the α-helical structure of NFL, but they caused a noticeable effects on the stability of the molecule. We also identified calorimetric domains in the NFL structure by using the differential scanning calorimetry. It was shown that the E90K replacement lead to the disappearance of the low-temperature thermal transition (domain 1). The mutations lead to changes in the enthalpy of melting of NFL domains, as well as lead to significant changes in the melting temperatures (Tm) of some calorimetric domains. Thus, despite the fact that all these amino acid substitutions are associated with the development of Charcot-Marie-Tooth neuropathy, and two of them are even located very close to each other in the coiled-coil domain 1A, they differently effects on the structure and stability of the NFL molecule.

About the authors

V. V Nefedova

Research Centre of Biotechnology of the Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia

D. S Yampolskaya

Research Centre of Biotechnology of the Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia

S. Y Kleymenov

Research Centre of Biotechnology of the Russian Academy of Sciences;Koltzov Institute of Developmental Biology, Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia;119334 Moscow, Russia

N. A Chebotareva

Research Centre of Biotechnology of the Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia

A. M Matyushenko

Research Centre of Biotechnology of the Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia

D. I Levitsky

Research Centre of Biotechnology of the Russian Academy of Sciences

Email: victoria.v.nefedova@mail.ru
119071 Moscow, Russia

References

  1. Herrmann, H., and Aebi, U. (2004) Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular Scaffolds, Annu. Rev. Biochem., 73, 749-789, doi: 10.1146/annurev.biochem.73.011303.073823.
  2. Kornreich, M., Avinery, R., Malka-Gibor, E., Laser-Azogui, A., and Beck, R. (2015) Order and disorder in intermediate filament proteins, FEBS Lett., 589 (19 Pt A), 2464-2476, doi: 10.1016/j.febslet.2015.07.024.
  3. Chernyatina, A. A., Nicolet, S., Aebi, U., Herrmann, H., and Strelkov, S. V. (2012) Atomic structure of the vimentin central α-helical domain and its implications for intermediate filament assembly, Proc. Natl. Acad. Sci. USA, 109, 13620-13625, doi: 10.1073/pnas.1206836109.
  4. Eldirany, S., Ho, M., Hinbest, A. J., Lomakin, I. B., and Bunick, C. G. (2019) Human keratin 1/10-1B tetramer structures reveal a knob-pocket mechanism in intermediate filament assembly, EMBO J., 38, e100741, doi: 10.15252/embj.2018100741.
  5. Strelkov, S. V., Herrmann, H., and Aebi, U., (2003) Molecular architecture of intermediate filaments, Bioessays, 25, 243-251, doi: 10.1002/bies.10246.
  6. Block, J., Schroeder, V., Pawelzyk, P., Willenbacher, N., and Koster, S. (2015) Physical properties of cytoplasmic intermediate filaments, Biochim. Biophys. Acta, 1853, 3053-3064, doi: 10.1016/j.bbamcr.2015.05.009.
  7. Herrmann, H., Haner, M., Brettel, M., Ku, N. O., and Aebi, U. (1999) Characterization of distinct early assembly units of different intermediate filament proteins, J. Mol. Biol., 286, 1403-1420, doi: 10.1006/jmbi.1999.2528.
  8. Brennich, M.E., Vainio, U., Wedig, T., Bauch, S., Herrmann, H., and Köster, S. (2019) Mutation-induced alterations of intra-filament subunit organization in vimentin filaments revealed by SAXS, Soft Matter, 15, 1999-2008, doi: 10.1039/c8sm02281j.
  9. Lee, C.-H., Kim, M.-S., Li, S., Leahy, D. J., and Coulombe, P. A. (2020) Structure-function analyses of a keratin heterotypic complex identify specific keratin regions involved in intermediate filament assembly, Structure, 28, 1-8, doi: 10.1016/j.str.2020.01.002.
  10. Laser-Azogui, A., Kornreich, M., Malka-Gibor, E., and Beck, R. (2015) Neurofilament assembly and function during neuronal development, Curr. Opin. Cell Biol., 32, 92-101, doi: 10.1016/j.ceb.2015.01.003.
  11. Veeranna, Amin, N. D., Ahn, N. G., Jaffe, H., Winters, C. A., Grant, P., and Pant, H. C. (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M, J. Neurosci., 18, 4008-4021, doi: 10.1523/JNEUROSCI.18-11-04008.1998.
  12. Athlan, E. S., and Mushynski, W. E. (1997) Heterodimeric associations between neuronal intermediate filament proteins, J. Biol. Chem., 272, 31073-31078, doi: 10.1074/jbc.272.49.31073.
  13. Garden, M. J., and Eagles, P. A. (1986) Chemical cross-linking analyses of ox neurofilaments, Biochem. J., 234, 587-591, doi: 10.1042/bj2340587.
  14. Sasaki, T., Gotow, T., Shiozaki, M., Sakaue, F., Saito, T., Julien, J.-P, Uchiyama, Y., and Hisanaga, S.-I. (2006) Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot-Marie-Tooth disease mutants, Hum. Mol. Genet., 15, 943-952, doi: 10.1093/hmg/ddl011.
  15. Yuan, A., Rao, M. V., Julien, J.-P., and Nixon, R. A. (2003) Neurofilament transport in vivo minimally requires hetero-oligomer formation, J. Neurosci., 23, 9452-9458, doi: 10.1523/JNEUROSCI.23-28-09452.2003.
  16. Houlden, H., and Reilly, M. M. (2006) Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease, Neuromolecular Med., 8, 43-62, doi: 10.1385/nmm:8:1-2:43.
  17. Yang, Y., Li-Qiang, Gu, Burnette, W. B., and Li, J. (2016) N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy, J. Neurol. Sci., 365, 46-47, doi: 10.1016/j.jns.2016.04.007.
  18. Rossor, A. M., Polke, J. M., Houlden, H., and Reilly, M. M. (2013) Clinical implications of genetic advances in Charcot-Marie-Tooth disease, Nat. Rev. Neurol., 9, 562-571, doi: 10.1038/nrneurol.2013.179.
  19. Stone, E. J., Kolb, S. J., and Brown, A. (2021) A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L, Cytoskeleton, 78, 97-110, doi: 10.1002/cm.21676.
  20. Brownlees, J., Ackerley, S., Grierson, A. J., Jacobsen, N. J. O., Shea, K., Anderton, B. H., Nigel Leigh, P., Shaw, C. E., and Miller, C. C. J. (2002) Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport, Hum. Mol. Genet., 11, 2837-2844, doi: 10.1093/hmg/11.23.2837.
  21. Perez-Olle, R., Jones, S. T., and Liem, R. K. H. (2004) Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models, Hum. Mol. Genet., 13, 2207-2220, doi: 10.1093/hmg/ddh236.
  22. Stone, E. J., Uchida, A., and Brown, A. (2019) Charcot-Marie-Tooth disease type 2E/1F mutant neurofilament proteins assemble into neurofilaments, Cytoskeleton (Hoboken), 76, 423-439, doi: 10.1002/cm.21566.
  23. Adebola, A. A., Gastri, T. D., He, C.-Z., Salvatierra, L. A., Zhao, J., Brown, K., Lin, C.-S., Worman, H. J., and Liem, R. K. H. (2014) Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth type 2E phenotype, Hum. Mol. Genet., 24, 2163-2174, doi: 10.1093/hmg/ddu736.
  24. Lee, I.-B., Kim, S.-K., Chung, S.-H., Kim, H., Kwon, T. K., Min, D. S., and Chang, J.-S. (2008) The effect of rod domain A148V mutation of neurofilament light chain on filament formation, BMB Rep., 41, 868-874, doi: 10.5483/bmbrep.2008.41.12.868.
  25. Jordanova, A., De Jonghe, P., Boerkoel, C. F., Takashima, H., De Vriendt, E., Ceuterick, C., Martin, J.-J., Butler, I. J., Mancias, P., Papasozomenos, S. Ch., Terespolsky, D., Potocki, L., Brown, C.W., Shy, M., Rita, D. A., Tournev, I., Kremensky, I., Lupski, J. R., and Timmerman, V. (2003) Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease, Brain, 126, 590-597, doi: 10.1093/brain/awg059.
  26. Nevzorov, I. A., and Levitsky, D. I. (2011) Tropomyosin: double helix from the protein world, Biochemistry (Moscow), 76, 1507-1527, doi: 10.1134/S0006297911130098.
  27. Nevzorov, I. A., Nikolaeva, O. P., Kainov, Y. A., Redwood, C. S., and Levitsky, D. I. (2011) Conserved noncanonical residue Gly-126 confers instability to the middle part of the tropomyosin molecule, J. Biol. Chem., 286, 15766-15772, doi: 10.1074/jbc.M110.209353.
  28. Kremneva, E., Boussouf, S., Nikolaeva, O., Maytum, R., Geeves, M. A., and Levitsky, D. I. (2004) Effects of two familial hypertrophic cardiomyopathy mutations in α-tropomyosin, Asp175Asn and Glu180Gly, on the thermal unfolding of actin-bound tropomyosin, Biophys. J., 87, 3922-3933, doi: 10.1529/biophysj.104.048793.
  29. Matyushenko, A. M., Shchepkin, D. V., Kopylova, G. V., Popruga, K. E., Artemova, N. V., Pivovarova, A. V., Bershitsky, S. Y., and Levitsky, D. I. (2017) Structural and functional effects of cardiomyopathy-causing mutations in troponin T-binding region of cardiac tropomyosin, Biochemistry, 56, 250-259, doi: 10.1021/acs.biochem.6b00994.
  30. Matyushenko, A. M., Artemova, N. V., Sluchanko, N. N., and Levitsky, D. I. (2015) Effects of two stabilizing substitutions, D137L and G126R, in the middle part of α-tropomyosin on the domain structure of its molecule, Biophys. Chem., 196, 77-85, doi: 10.1016/j.bpc.2014.10.001.
  31. Nevzorov, I., Redwood, C., and Levitsky, D. (2008) Stability of two β-tropomyosin isoforms: effects of mutation Arg91Gly, J. Muscle Res. Cell Motil., 29, 173-176, doi: 10.1007/s10974-009-9171-3.
  32. Schuck, P., and Rossmanith, P. (2000) Determination of the sedimentation coefficient distribution by least-squares boundary modeling, Biopolymers, 54, 328-341, doi: 10.1002/1097-0282(20001015)54:5<328::AID-BIP40>3.0.CO;2-P.
  33. Freire, E., and Biltonen, R. L. (1978) Statistical mechanical deconvolution of thermal transitions in macromolecules. I. Theory and application to homogeneous systems, Biopolymers, 17, 463-479, doi: 10.1002/bip.1978.360170212.
  34. Nefedova, V. V., Sudnitsyna, M. V., and Gusev, N. B. (2017) Interaction of small heat shock proteins with light component of neurofilaments (NFL), Cell Stress Chaperones, 22, 467-479, doi: 10.1007/s12192-016-0757-6.
  35. Mücke, N., Wedig, T., Bürer, A., Marekov, L. N., Steinert, P. M., Langowski, J., Aebi, U., and Herrmann, H. (2004) Molecular and biophysical characterization of assembly-starter units of human vimentin, J. Mol. Biol., 340, 97-114, doi: 10.1016/j.jmb.2004.04.039.
  36. Wickert, U., Mücke, N., Wedig, T., Müller, S. A., Aebi, U., and Herrmann, H. (2005) Characterization of the in vitro co-assembly process of the intermediate filament proteins vimentin and desmin: mixed polymers at all stages of assembly, Eur. J. Cell Biol., 84, 379-391, doi: 10.1016/j.ejcb.2005.01.004.
  37. Soellner, P., Quinlan, R. A., and Franke, W. W. (1985) Identification of a distinct soluble subunit of an intermediate filament protein: tetrameric vimentin from living cells, Proc. Natl. Acad. Sci. USA, 82, 7929-7933, doi: 10.1073/pnas.82.23.7929.
  38. Minin, A. A., and Moldaver, M. V. (2008) Intermediate vimentin filaments and their role in intracellular organelle distribution, Biochemistry (Moscow), 73, 1453-1466, doi: 10.1134/s0006297908130063.
  39. Meier, M., Padilla, G. P., Herrmann, H., Wedig, T., Hergt, M., Patel, T. R., Stetefeld, J., Aebi, U., and Burkhard, P. (2009) Vimentin coil 1A - a molecular switch involved in the initiation of filament elongation, J. Mol. Biol., 390, 245-261, doi: 10.1016/j.jmb.2009.04.067.
  40. Vermeire, P.-J., Stalmans, G., Lilina, A. V., Fiala, J., Novak, P., Herrmann, H., and Strelkov, S. V. (2021) Molecular interactions driving intermediate filament assembly, Cells, 10, 2457, doi: 10.3390/cells10092457.
  41. Lilina, A. V., Leekens, S., Hashim, H. M., Vermeire, P.-J., Harvey, J. N., Strelkov, S. V. (2022) Stability profile of vimentine rod domain, Protein Sci., 31, e4505, doi: 10.1002/pro.4505.
  42. Premchandar, A., Mücke, N., Poznański, J., Wedig, T., Kaus-Drobek, M., Herrmann, H., and Dadlez, M. (2016) Structural dynamics of the vimentin coiled-coil contact regions involved in filament assembly as revealed by hydrogen-deuterium exchange, J. Biol. Chem., 291, 24931-24950, doi: 10.1074/jbc.M116.748145.
  43. Simm, D., Hatje, K., and Kollmar, M. (2015) Waggawagga: comparative visualization of coiled-coil predictions and detection of stable single α-helices (SAH domains), Bioinformatics, 31, 767-769, doi: 10.1093/bioinformatics/btu700.

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