Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH
Abstract
:1. Introduction
2. Results and Discussion
2.1. Structural Stability and Deviation from the Native Structure
2.2. HA and Native Sheet Conformational Changes
2.3. Structural Changes and Alterations in Native Polar Contacts
pH | Simulation | HA relevant contacts | S2 relevant contacts | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Y149-D202 | R156-D202 | E146-R208 | K194-E196 | H155-E196 | Y162-T183 | Y162-E186 | Y163-E221 | E186-H187 | ||
Neutral | Average | 90.7 | 51.4 | 73.7 | 52.8 | 0.0 | 29.7 | 28.1 | 70.9 | 0.0 |
Mid | 1 | 0.0 | 100.0 | 100.0 | 100.0 | 100.0 | 20.1 | 29.3 | 99.9 | 0.0 |
Low | 1 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 84.4 | 0.0 | 2.9 | 0.0 |
2.3.1. Polar Contacts with HA
2.3.2. Polar Contacts with S2
2.4. Solvent Exposure of Hydrophobic Regions
2.5. Formation of Nonnative β-Strands
2.5.1. Hydrophobic Contacts at Low pH
2.5.2. Polar Contacts at Mid-pH
3. Experimental Section
4. Conclusions
Acknowledgments
Conflicts of Interest
References and Notes
- Prusiner, S.B.; Scott, M.R.; DeArmond, S.J.; Cohen, F.E. Prion Protein Biology. Cell 1998, 93, 337–348. [Google Scholar] [CrossRef]
- Prusiner, S.B. Molecular biology of prion diseases. Science 1991, 252, 1515–1522. [Google Scholar] [CrossRef]
- Almond, J.; Pattison, J. Human BSE. Nature 1997, 389, 437–438. [Google Scholar] [CrossRef]
- Collinge, J. Variant Creutzfeldt-Jakob disease. The Lancet 1999, 354, 317–323. [Google Scholar] [CrossRef]
- Australia lures Japanese beef buyers. Available online: http://www.abc.net.au/news/2003-12-30/australia-lures-japanese-beef-buyers/112748 (accessed on 1 November 2013).
- Hosszu, L.L.P.; Tattum, M.H.; Jones, S.; Trevitt, C.R.; Wells, M.A.; Waltho, J.P.; Collinge, J.; Jackson, G.S.; Clarke, A.R. The H187R Mutation of the Human Prion Protein Induces Conversion of Recombinant Prion Protein to the PrPSc-like Form. Biochemistry 2010, 49, 8729–8738. [Google Scholar] [CrossRef]
- Adrover, M.; Pauwels, K.; Prigent, S.; Chiara, C.; Xu, Z.; Chapuis, C.; Pastore, A.; Rezaei, H. Prion Fibrillization Is Mediated by a Native Structural Element That Comprises Helices H2 and H3. J. Biol. Chem. 2010, 285, 21004–21012. [Google Scholar]
- Gerber, R.; Tahiri‐Alaoui, A.; Hore, P. Conformational pH dependence of intermediate states during oligomerization of the human prion protein. Protein Sci. 2008, 17, 537–544. [Google Scholar]
- Hornemann, S.; Glockshuber, R. A scrapie-like unfolding intermediate of the prion protein domain PrP(121–231) induced by acidic pH. Proc. Natl. Acad. Sci. 1998, 95, 6010–6014. [Google Scholar]
- Swietnicki, W.; Petersen, R.; Gambetti, P.; Surewicz, W.K. pH-dependent Stability and Conformation of the Recombinant Human Prion Protein PrP(90–231). J. Biol. Chem. 1997, 272, 27517–27520. [Google Scholar]
- Harris, D.A. Trafficking, Turnover and Membrane Topology of PrP Protein Function in Prion Disease. Br. Med. Bull. 2003, 66, 71–85. [Google Scholar] [CrossRef]
- Mironov, A.; Latawiec, D.; Wille, H.; Bouzamondo-Bernstein, E.; Legname, G.; Williamson, R.A.; Burton, D.; DeArmond, S.J.; Prusiner, S.B.; Peters, P.J. Cytosolic Prion Protein in Neurons. J. Neurosci. 2003, 23, 7183–7193. [Google Scholar]
- Roos, A.; Boron, W.F. Intracellular pH. Physiol. Rev. 1982, 62, 1377–1377. [Google Scholar]
- Aubry, L.; Klein, G.; Martiel, J.L.; Satre, M. Kinetics of endosomal pH evolution in Dictyostelium discoideum amoebae. Study by fluorescence spectroscopy. J. Cell Sci. 1993, 105, 861–866. [Google Scholar]
- Arnold, J.E.; Tipler, C.; Laszlo, L.; Hope, J.; Landon, M.; Mayer, R.J. The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain. J. Pathol. 1995, 176, 403–411. [Google Scholar] [CrossRef]
- Borchelt, D.R.; Taraboulos, A.; Prusiner, S.B. Evidence for synthesis of scrapie prion proteins in the endocytic pathway. J. Biol. Chem. 1992, 267, 16188–16199. [Google Scholar]
- Caughey, B.; Raymond, G.J.; Ernst, D.; Race, R.E. N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J. Virol. 1991, 65, 6597–6603. [Google Scholar]
- Godsave, S.F.; Wille, H.; Kujala, P.; Latawiec, D.; DeArmond, S.J.; Serban, A.; Prusiner, S.B.; Peters, P.J. Cryo-immunogold electron microscopy for prions: toward identification of a conversion site. J. Neurosci. Off. J. Soc. Neurosci. 2008, 28, 12489–12499. [Google Scholar] [CrossRef]
- Matsunaga, Y.; Peretz, D.; Williamson, A.; Burton, D.; Mehlhorn, I.; Groth, D.; Cohen, F.E.; Prusiner, S.B.; Baldwin, M.A. Cryptic epitopes in N-terminally truncated prion protein are exposed in the full-length molecule: dependence of conformation on pH. Proteins 2001, 44, 110–118. [Google Scholar] [CrossRef]
- James, T.L.; Liu, H.; Ulyanov, N.B.; Farr-Jones, S.; Zhang, H.; Donne, D.G.; Kaneko, K.; Groth, D.; Mehlhorn, I.; Prusiner, S.B.; Cohen, F.E. Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc. Natl. Acad. Sci. 1997, 94, 10086–10091. [Google Scholar] [CrossRef]
- Riek, R.; Hornemann, S.; Wider, G.; Billeter, M.; Glockshuber, R.; Wüthrich, K. NMR structure of the mouse prion protein domain PrP(121–231). Nature 1996, 382, 180–182. [Google Scholar] [CrossRef]
- Lopez Garcia, F. NMR structure of the bovine prion protein. Proc. Natl. Acad. Sci. 2000, 97, 8334–8339. [Google Scholar] [CrossRef]
- Zahn, R.; Liu, A.; Lührs, T.; Riek, R.; von Schroetter, C.; López García, F.; Billeter, M.; Calzolai, L.; Wider, G.; Wüthrich, K. NMR solution structure of the human prion protein. Proc. Natl. Acad. Sci. 2000, 97, 145–50. [Google Scholar] [CrossRef]
- Pan, K.M.; Baldwin, M.; Nguyen, J.; Gasset, M.; Serban, A.; Groth, D.; Mehlhorn, I.; Huang, Z.; Fletterick, R.J.; Cohen, F.E. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. 1993, 90, 10962–10966. [Google Scholar] [CrossRef]
- Caughey, B.W.; Dong, A.; Bhat, K.S.; Ernst, D.; Hayes, S.F.; Caughey, W.S. Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy. Biochemistry 1991, 30, 7672–7680. [Google Scholar] [CrossRef]
- Jackson, G.S.; Hill, A.F.; Joseph, C.; Hosszu, L.; Power, A.; Waltho, J.P.; Clarke, A.R.; Collinge, J. Multiple folding pathways for heterologously expressed human prion protein. Biochim. Biophys. Acta 1999, 1431, 1–13. [Google Scholar]
- Van der Kamp, M.W.; Daggett, V. Influence of pH on the human prion protein: insights into the early steps of misfolding. Biophys. J. 2010, 99, 2289–2298. [Google Scholar] [CrossRef]
- DeMarco, M.L.; Daggett, V. Molecular mechanism for low pH triggered misfolding of the human prion protein. Biochemistry 2007, 46, 3045–3054. [Google Scholar] [CrossRef]
- DeMarco, M.L.; Daggett, V. Characterization of cell-surface prion protein relative to its recombinant analogue: insights from molecular dynamics simulations of diglycosylated, membrane-bound human prion protein. J. Neurochem. 2009, 109, 60–73. [Google Scholar] [CrossRef]
- Alonso, D.O.V.; DeArmond, S.J.; Cohen, F.E.; Daggett, V. Mapping the early steps in the pH-induced conformational conversion of the prion protein. Proc. Natl. Acad. Sci. 2001, 98, 2985–2989. [Google Scholar]
- DeMarco, M.L.; Daggett, V. From conversion to aggregation: Protofibril formation of the prion protein. Proc. Natl. Acad. Sci. 2004, 101, 2293–2298. [Google Scholar] [CrossRef]
- Alonso, D.O.V.; An, C.; Daggett, V. Simulations of biomolecules: Characterization of the early steps in the pH-induced conformational conversion of the hamster, bovine and human forms of the prion protein. Philos. Trans. R. Soc. -Ser. Math. Phys. Eng. Sci. 2002, 360, 1165–1178. [Google Scholar] [CrossRef]
- Scouras, A.D.; Daggett, V. Species variation in PrPSc protofibril models. J. Mater. Sci. 2008, 43, 3625–3637. [Google Scholar] [CrossRef]
- Watanabe, Y.; Inanami, O.; Horiuchi, M.; Hiraoka, W.; Shimoyama, Y.; Inagaki, F.; Kuwabara, M. Identification of pH-sensitive regions in the mouse prion by the cysteine-scanning spin-labeling ESR technique. Biochem. Biophys. Res. Commun. 2006, 350, 549–556. [Google Scholar] [CrossRef]
- Paramithiotis, E.; Pinard, M.; Lawton, T.; LaBoissiere, S.; Leathers, V.L.; Zou, W.-Q.; Estey, L.A.; Lamontagne, J.; Lehto, M.T.; Kondejewski, L.H.; Francoeur, G.P.; Papadopoulos, M.; Haghighat, A.; Spatz, S.J.; Head, M.; Will, R.; Ironside, J.; O’Rourke, K.; Tonelli, Q.; Ledebur, H.C.; Chakrabartty, A.; Cashman, N.R. A prion protein epitope selective for the pathologically misfolded conformation. Nat. Med. 2003, 9, 893–899. [Google Scholar] [CrossRef]
- Calzolai, L.; Zahn, R. Influence of pH on NMR structure and stability of the human prion protein globular domain. J. Biol. Chem. 2003, 278, 35592–35596. [Google Scholar] [CrossRef]
- Lingenheil, M.; Denschlag, R.; Tavan, P. Highly polar environments catalyze the unfolding of PrPC helix 1. Eur. Biophys. J. 2010, 39, 1177–1192. [Google Scholar] [CrossRef]
- Chen, W.; van der Kamp, M.W.; Daggett, V. Diverse effects on the native β-sheet of the human prion protein due to disease-associated mutations. Biochemistry 2010, 49, 9874–9881. [Google Scholar] [CrossRef]
- Haire, L.F.; Whyte, S.M.; Vasisht, N.; Gill, A.C.; Verma, C.; Dodson, E.J.; Dodson, G.G.; Bayley, P.M. The Crystal Structure of the Globular Domain of Sheep Prion Protein. J. Mol. Biol. 2004, 336, 1175–1183. [Google Scholar] [CrossRef]
- Van der Kamp, M.W.; Daggett, V. Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding. J. Mol. Biol. 2010, 404, 732–748. [Google Scholar] [CrossRef]
- Julien, O.; Chatterjee, S.; Thiessen, A.; Graether, S.P.; Sykes, B.D. Differential stability of the bovine prion protein upon urea unfolding. Protein Sci. 2009, 18, 2172–2182. [Google Scholar] [CrossRef]
- Hirschberger, T.; Stork, M.; Schropp, B.; Winklhofer, K.F.; Tatzelt, J.; Tavan, P. Structural instability of the prion protein upon M205S/R mutations revealed by molecular dynamics simulations. Biophys. J. 2006, 90, 3908–3918. [Google Scholar] [CrossRef]
- Hafner-Bratkovič, I.; Bester, R.; Pristovšek, P.; Gaedtke, L.; Veranič, P.; Gašperšič, J.; Manček-Keber, M.; Avbelj, M.; Polymenidou, M.; Julius, C.; Aguzzi, A.; Vorberg, I.; Jerala, R. Globular domain of the prion protein needs to be unlocked by domain swapping to support prion protein conversion. J. Biol. Chem. 2011, 286, 12149–12156. [Google Scholar] [CrossRef] [Green Version]
- Eghiaian, F.; Daubenfeld, T.; Quenet, Y.; Audenhaege, M. van; Bouin, A.-P.; Rest, G. van der; Grosclaude, J.; Rezaei, H. Diversity in prion protein oligomerization pathways results from domain expansion as revealed by hydrogen/deuterium exchange and disulfide linkage. Proc. Natl. Acad. Sci. 2007, 104, 7414–7419. [Google Scholar] [CrossRef]
- Jones, M.; McLoughlin, V.; Connolly, J.G.; Farquhar, C.F.; MacGregor, I.R.; Head, M.W. Production and characterization of a panel of monoclonal antibodies against native human cellular prion protein. Hybridoma 2009, 28, 13–20. [Google Scholar] [CrossRef]
- Vanik, D.L.; Surewicz, W.K. Disease-associated F198S mutation increases the propensity of the recombinant prion protein for conformational conversion to scrapie-like form. J. Biol. Chem. 2002, 277, 49065–49070. [Google Scholar] [CrossRef]
- Liemann, S.; Glockshuber, R. Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Biochemistry 1999, 38, 3258–3267. [Google Scholar] [CrossRef]
- Palmer, M.S.; Dryden, A.J.; Hughes, J.T.; Collinge, J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 1991, 352, 340–342. [Google Scholar] [CrossRef]
- Schätzl, H.M.; Wopfner, F.; Gilch, S.; von Brunn, A.; Jäger, G. Is codon 129 of prion protein polymorphic in human beings but not in animals? The Lancet 1997, 349, 1603–1604. [Google Scholar] [CrossRef]
- Green, K.M.; Browning, S.R.; Seward, T.S.; Jewell, J.E.; Ross, D.L.; Green, M.A.; Williams, E.S.; Hoover, E.A.; Telling, G.C. The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation. J. Gen. Virol. 2008, 89, 598–608. [Google Scholar] [CrossRef]
- Chen, W.; Van der Kamp, M.W.; Daggett, V. Structural and dynamic properties of the human prion protein. Biophys. J. 2014, in press. [Google Scholar]
- Forloni, G.; Angeretti, N.; Chiesa, R.; Monzani, E.; Salmona, M.; Bugiani, O.; Tagliavini, F. Neurotoxicity of a prion protein fragment. Nature 1993, 362, 543–546. [Google Scholar]
- Selvaggini, C.; Degioia, L.; Cantu, L.; Ghibaudi, E.; Diomede, L.; Passerini, F.; Forloni, G.; Bugiani, O.; Tagliavini, F.; Salmona, M. Molecular Characteristics of a Protease-Resistant, Amyloidogenic and Neurotoxic Peptide Homologous to Residues 106-126 of the Prion Protein. Biochem. Biophys. Res. Commun. 1993, 194, 1380–1386. [Google Scholar] [CrossRef]
- De Gioia, L.; Selvaggini, C.; Ghibaudi, E.; Diomede, L.; Bugiani, O.; Forloni, G.; Tagliavini, F.; Salmona, M. Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein. J. Biol. Chem. 1994, 269, 7859–7862. [Google Scholar]
- Brown, D.R.; Schmidt, B.; Kretzschmar, H.A. Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 1996, 380, 345–347. [Google Scholar] [CrossRef]
- Armen, R.S.; Bernard, B.M.; Day, R.; Alonso, D.O.V.; Daggett, V. Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases. Proc. Natl. Acad. Sci. 2005, 102, 13433–13438. [Google Scholar]
- Daggett, V. Alpha-sheet: The toxic conformer in amyloid diseases? Acc. Chem. Res. 2006, 39, 594–602. [Google Scholar] [CrossRef]
- Baylis, M.; Goldmann, W. The Genetics of Scrapie in Sheep and Goats. Curr. Mol. Med. 2004, 4, 385–396. [Google Scholar] [CrossRef]
- Gambetti, P.; Parchi, P.; Petersen, R.B.; Chen, S.G.; Lugaresi, E. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol. 1995, 5, 43–51. [Google Scholar] [CrossRef]
- Gsponer, J.; Ferrara, P.; Caflisch, A. Flexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations. J. Mol. Graph. Model. 2001, 20, 169–182. [Google Scholar] [CrossRef]
- Kaneko, K.; Zulianello, L.; Scott, M.; Cooper, C.M.; Wallace, A.C.; James, T.L.; Cohen, F.E.; Prusiner, S.B. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc. Natl. Acad. Sci. 1997, 94, 10069–10074. [Google Scholar] [CrossRef]
- Helmus, J.J.; Surewicz, K.; Nadaud, P.S.; Surewicz, W.K.; Jaroniec, C.P. Molecular conformation and dynamics of the Y145Stop variant of human prion protein in amyloid fibrils. Proc. Natl. Acad. Sci. 2008, 105, 6284–6289. [Google Scholar]
- Abalos, G.C.; Cruite, J.T.; Bellon, A.; Hemmers, S.; Akagi, J.; Mastrianni, J.A.; Williamson, R.A.; Solforosi, L. Identifying key components of the PrPC-PrPSc replicative interface. J. Biol. Chem. 2008, 283, 34021–34028. [Google Scholar] [CrossRef]
- Norstrom, E.M.; Mastrianni, J.A. The AGAAAAGA palindrome in PrP is required to generate a productive PrPSc-PrPC complex that leads to prion propagation. J. Biol. Chem. 2005, 280, 27236–27243. [Google Scholar] [CrossRef]
- Muramoto, T.; Scott, M.; Cohen, F.E.; Prusiner, S.B. Recombinant scrapie-like prion protein of 106 amino acids is soluble. Proc. Natl. Acad. Sci. 1996, 93, 15457–15462. [Google Scholar] [CrossRef]
- Langella, E.; Improta, R.; Crescenzi, O.; Barone, V. Assessing the acid–base and conformational properties of histidine residues in human prion protein (125–228) by means of pKa calculations and molecular dynamics simulations. Proteins Struct. Funct. Bioinforma. 2006, 64, 167–177. [Google Scholar] [CrossRef]
- Beck, D.A.C.; McCully, M.E.; Alonso, D.O.V.; Daggett, V. in lucem Molecular Mechanics(ilmm). 2000-2014. [Google Scholar]
- Levitt, M.; Hirshberg, M.; Sharon, R.; Daggett, V. Potential energy function and parameters for simulations of the molecular dynamics of proteins and nucleic acids in solution. Comput. Phys. Commun. 1995, 91, 215–231. [Google Scholar] [CrossRef]
- Beck, D.A.C.; Daggett, V. Methods for molecular dynamics simulations of protein folding/unfolding in solution. Methods 2004, 34, 112–120. [Google Scholar] [CrossRef]
- Kell, G.S. Precise representation of volume properties of water at one atmosphere. J. Chem. Eng. Data 1967, 12, 66–69. [Google Scholar] [CrossRef]
- Levitt, M.; Hirshberg, M.; Sharon, R.; Laidig, K.E.; Daggett, V. Calibration and testing of a water model for simulation of the molecular dynamics of proteins and nucleic acids in solution. J. Phys. Chem. B 1997, 101, 5051–5061. [Google Scholar]
- Beck, D.A.C.; Armen, R.S.; Daggett, V. Cutoff size does strongly influence molecular dynamics results on solvated polypeptides. Biochemistry 2005, 44, 5856–5860. [Google Scholar]
- Kabsch, W.; Sander, C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983, 22, 2577–2637. [Google Scholar] [CrossRef]
- Lee, B.; Richards, F.M. The interpretation of protein structures: Estimation of static accessibility. J. Mol. Biol. 1971, 55, 379–400. [Google Scholar] [CrossRef]
- Humphrey, W.; Dalke, A.; Schulten, K. VMD – Visual Molecular Dynamics. J. Mol. Graph. 1996, 14, 33–38. [Google Scholar] [CrossRef]
- DeMarco, M.L.; Silveira, J.; Caughey, B.; Daggett, V. Structural properties of prion protein protofibrils and fibrils: An experimental assessment of atomic models. Biochemistry 2006, 45, 15573–15582. [Google Scholar] [CrossRef]
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Cheng, C.J.; Daggett, V. Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH. Biomolecules 2014, 4, 181-201. https://doi.org/10.3390/biom4010181
Cheng CJ, Daggett V. Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH. Biomolecules. 2014; 4(1):181-201. https://doi.org/10.3390/biom4010181
Chicago/Turabian StyleCheng, Chin Jung, and Valerie Daggett. 2014. "Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH" Biomolecules 4, no. 1: 181-201. https://doi.org/10.3390/biom4010181
APA StyleCheng, C. J., & Daggett, V. (2014). Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH. Biomolecules, 4(1), 181-201. https://doi.org/10.3390/biom4010181