跳至主要内容

Human Prion Protein Conformational Changes Susceptibility: A Molecular Dynamics Simulation Study

Read full paper at:
http://www.scirp.org/journal/PaperInformation.aspx?PaperID=51126#.VFbQbGfHRK0

Prion proteins are related to the development of incurable and invariably fatal neurodegenerative diseases in humans and animals. The pathogenicity involves the conversion of the host-encoded-alpha rich isoform of prion protein, PrPC, into a misfolded beta-strand rich conformer, PrPSc. Although it has already been described that many punctual mutations alter the stability of PrPC, making it more prone to adopt an abnormal misfolded structure, the majority of cases reported among general population are sporadic in wild-type organisms. Thus, in this work we studied the dynamics and stability profiles of wild-type human prion protein by Molecular Dynamics (MD) simulation at different solvent temperatures. This analysis brought out certain residues and segments of the prion protein as critical to conformational changes; these results are consistent with experimental reports showing that protein mutants in those positions are related to the development of disease.
Cite this paper
Mandujano-Rosas, L. , Osorio-González, D. , Reyes-Romero, P. and Mulia-Rodríguez, J. (2014) Human Prion Protein Conformational Changes Susceptibility: A Molecular Dynamics Simulation Study. Open Journal of Biophysics, 4, 169-175. doi: 10.4236/ojbiphy.2014.44016. 
 

[1] Rane, N.S., Chakrabarti, O., Feigenbaum, L. and Hegde, R. (2010) Signal Sequence Insufficiency Contributes to Neurodegeneration Caused by Transmembrane Prion Protein. The Journal of Cell Biology, 188, 515-526.
http://dx.doi.org/10.1083/jcb.200911115
[2] Haraguchi, T., Fisher, S., Olofsson, S., Endo, T., Groth, D., Tarentino, A., Borchelt, D.R., Teplow, D., Hood, L., Burlingame, A., Lycke, E., Kobata, A. and Prusiner, S.B. (1989) Asparagine-Linked Glycosylation of the Scrapie and Cellular Prion Proteins. Archives of Biochemistry and Biophysics, 274, 1-13.
http://dx.doi.org/10.1016/0003-9861(89)90409-8
[3] Stahl, N., Borchelt, D.R., Hsiao, K. and Prusiner, S.B. (1987) Scrapie Prion Protein Contains a Phosphatidylinositol Glycolipid. Cell, 51, 229-240.
http://dx.doi.org/10.1016/0092-8674(87)90150-4
[4] Stimson, E., Hope, J., Chong, A. and Burlingame, A.L. (1999) Site-Specific Characterization of the N-Linked Glycans of Murine Prion Protein by High-Performance Liquid Chromatography/Electrospray Mass Spectrometry and Exoglycosidase Digestions. Biochemistry, 38, 4885-4895.
http://dx.doi.org/10.1021/bi982330q
[5] Zhou, Z. and Xiao, G. (2013) Conformational Conversion of Prion Protein in Prion Diseases. Acta Biochimica et BiophysicaSinica, 45, 465-476.
http://dx.doi.org/10.1093/abbs/gmt027
[6] Ranjan-Maiti, N. and Surewicz, W.K. (2001) The Role of Disulfide Bridge in the Folding and Stability of the Recombinant Human Prion Protein. The Journal of Biological Chemistry, 276, 2427-2431.
http://dx.doi.org/10.1074/jbc.M007862200
[7] Coleman, B.M., Harrison, C.F., Guo, B., Masters, C.L., Barnham, K.J., Lawson, V.A. and Hill, H.F. (2014) Pathogenic Mutations within the Hydrophobic Domain of the Prion Protein Lead to the Formation of the Protease-Sensitive Prion Species with Increased Lethality. Journal of Virology, 88, 2690-2703.
http://dx.doi.org/10.1128/JVI.02720-13
[8] Prusiner, S.B. (1982) Novel Proteinaceous Infectious Particles Cause Scrapie. Science, 216, 136-144.
http://dx.doi.org/10.1126/science.6801762
[9] Zahn, R., Liu, A., Luhrs, T., Riek, R., von Schroetter, C., Lopez Garcia, F., Billeter, M., Calzolai, L., Wider, G. and Wuthrich, K. (2000) NMR Solution Structure of the Human Prion Protein. Proceedings of the National Academy of Sciences U.S.A., 97, 145-150.
http://dx.doi.org/10.1073/pnas.97.1.145
[10] Rossetti, G., Cong, X., Caliandro, R., Legname, G. and Carloni, P. (2011) Common Structural Traits Across Pathogenic Mutants of the Human Prion Protein and Their Implications for Familial Prion Disorders. Journal of Molecular Biology, 411, 700-712.
http://dx.doi.org/10.1016/j.jmb.2011.06.008
[11] Kiachopoulos, S., Bracher, A., Winklhofer, K.F. and Talzet, J. (2005) Pathogenic Mutations Located at the Hydrophobic Core of the Prion Protein Interfere with Folding and Attachment of the Glycosylphosphatidylinositol Anchor. The Journal of Biological Chemistry, 280, 9320-9329.
http://dx.doi.org/10.1074/jbc.M412525200
[12] Cheng, W., van der Kamp, M.W. and Daggett, V. (2014) Structural and Dynamic Properties of the Human Prion Protein. Biophysical Journal, 106, 1152-1163.
http://search.proquest.com/docview/1508983494?accountid=37347
http://dx.doi.org/10.1016/j.bpj.2013.12.053
[13] Ilc, G., Giachin, G., Jaremko, M., Jaremko, L., Benetti, F., Plavec, J., Zhukov, I. and Legname, G. (2010) NMR Structure of the Human Prion Protein with the Pathological Q212P Mutation Reveals Unique Structural Features. PLoS ONE, 5, e11715.
http://dx.doi.org/10.1371/journal.pone.0011715
[14] Tatzelt, J., Ed. (2011) Topics in Current Chemistry 305: Prion Proteins. Springer Berlin-Heidelberg, Berlin.
[15] Taylor, D.R., Whitehouse, I.J. and Hooper, N.M. (2009) Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation. PLoS Pathogens, 5, e1000666.
http://dx.doi.org/10.1371/journal.ppat.1000666
[16] Elmallah, M.I.Y., Borgmeyer, U., Betzel, C. and Redecke, L. (2013) Impact of Methionine Oxidation as an Initial Event on the Pathway of Human Prion Protein Conversion. Prion, 7, 404-411.
http://dx.doi.org/10.4161/pri.26745
[17] Mani, K., Cheng, F., Havsmark, B., Jonsson, M., Belting, M. and Fransson, L.A. (2003) Prion, Amyloid Beta-Derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-Dependent Autocleavage of Glypican-1 Heparan Sulfate. The Journal of Biological Chemistry, 278, 38956-38965.
http://dx.doi.org/10.1074/jbc.M300394200
[18] Wu, D., Zhang, W., Luo, Q., Luo, K., Huang, L., Wang, W., Huang, T., Chen, R., Lin, Y., Pang, D. and Xiao, G. (2010) Copper (II) Promotes the Formation of Soluble Neurotoxic PrP Oligomers in Acidic Environment. The Journal of Cell Biochemistry, 111, 627-633.
http://dx.doi.org/10.1002/jcb.22743
[19] Zhong, L. (2010) Exposure of Hydrophobic Core in Human Prion Protein Pathogenic Mutant H187R. Journal of Biomolecular Structure Dynamics, 28, 355-361.
http://dx.doi.org/10.1080/07391102.2010.10507365
[20] Cheng, C.J. and Dagget, V. (2014) Different Misfolding Mechanisms Converge on Common Conformational Changes: Human Prion Protein Pathogenic Mutants Y218N and E196K. Prion, 8, 125-135.
http://dx.doi.org/10.4161/pri.27807
[21] Hess, B., Kutzner, C., van der Spoel, D. and Lindahl, E. (2008) GROMACS 4: Algorithms for Highly Efficient, Load Balanced and Scalable Molecular Simulation. Journal of Chemical Theory and Computation, 4, 435-447.
http://dx.doi.org/10.1021/ct700301q
[22] Hess, B. (2002) Determining the Shear Viscosity of Model Liquids from Molecular Dynamics. The Journal of Chemical Physics, 116, 209-217.
http://dx.doi.org/10.1063/1.1421362                       eww141103lx
标签：

评论

发表评论

此博客中的热门博文

Does Immigration Promote the Investment of the Monopolistic Firm?

In the present paper, we examine the effect of increasing uncertainty of immigrants’ growth on the optimal timing of investment of a firm that has a monopolistic power over the labor market. It is revealed that when the uncertainty of immigrants’ growth is more than a threshold level, increasing uncertainty of immigrants’ growth accelerates the optimal timing of firms’ investment and enhances the economic growth, even if the uncertainty of immigrants’ growth is formulated by the geometric Brownian motion, which is in sharp contrast to the standard result that an increase in the uncertainty postpones the optimal timing. With an increase in the immigrants over the past ten years, workforces in the host countries have been growing significantly to the extent that the immigrants represent 70% of the increase in the workforce in Europe, and 47% in the United States as OECD indicates. In the present paper, we attempted to investigate the effect of increased uncertainty caused by the growi...
发表评论
阅读全文

Education Policy Implementation: A Mechanism for Enhancing Primary Education Development in Zanzibar

Education is one of the fundamental rights of individuals; therefore, the government of a country needs to develop and strengthen educational policy and quality as well as to ensure that everyone has equal access to basic education. The improvement of access and quality of education in the world is becoming as an essential factor in development, whereas the basic education (primary school), is acknowledged as a foundation of the higher educational development for every country. To fulfill this goal, governments introduce several policies and procedures; however, it requires some reforms and participation from the politician, policymakers, and other stakeholders to re-examine educational policy so that it can lead to multiplication and betterment of the reforms. Educational reforms actually focus on accountability. A positive educational development and reform is very challenging and needs more effort and strategy on how to use and utilize the resources effectively as such it can achie...
发表评论
阅读全文