Abstract
Toxicity of the prion molecule is a result of transmission of conformational change by direct contact with malignant misfolded molecule. The aim of this study is analyze the role of D278N mutation in promoting preferential oligomerization modes. Proteins exist as ensembles in equilibrium between different structural and dynamic states, including functionally relevant conformers as the most populated states as well as malfunctioning conformers as less populated states. Furthermore, the existence of different conformations allows protein oligomerization with condition-specific affinities. The maintenance of a particular role requires specific conversion between multiple stable states. Protein-protein binding may facilitate or may be a necessary condition of structural adaptation. In the case of prion disease, protein-protein interactions, resulting in prion agglomeration, have toxic effect. How exactly increased concentrations of prion oligomers trigger mechanisms leading to neuronal death is not known. Nevertheless, first oligomerization and second aggregate recognition are likely sequence of events that have to happen before any pathological condition may arise. Here, we carry out structural and dynamic analyses of the effect of disease-causing mutations on the dimerization and tetramerization of prion molecule as the first step in aggregate formation. D178N mutation has almost no effect on the monomeric structure but helps to stabilize the dimer, which consequently facilitates tetramer formation and stability.
Acknowledgments
The author thanks Dr. Vivien Yee for providing the tetramer structure of D178N prion molecule.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1 Aguzzi A, Calella AM. Prions: protein aggregation and infectious diseases. Physiol Rev 2009;89:1105–52.10.1152/physrev.00006.2009Search in Google Scholar
2 Soto C, Satani N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol Med 2010;17:14–24.10.1016/j.molmed.2010.09.001Search in Google Scholar
3 Flechsig E, Weissmann C. The role of PrP in health and disease. Curr Mol Med 2004;4:337–53.10.2174/1566524043360645Search in Google Scholar
4 Lee S, Antony L, Hartmann R, Knaus KJ, Surewicz K, Surewicz WK, et al. Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. EMBO J 2010;29:251–62.10.1038/emboj.2009.333Search in Google Scholar
5 Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol 1997;273:729–39.10.1006/jmbi.1997.1348Search in Google Scholar
6 Chen Y, He Y-J, Wu M, Yan G, Li Y, Zhang J, et al. Insight into the stability of cross-beta amyloid fibril from molecular dynamics simulation. Biopolymers 2010;93:578–86.Search in Google Scholar
7 Hirschberger T, Stork M, Schropp B, Winklhofer KF, Tatzelt J, Tavan P. Structural instability of the prion protein upon M205S/R mutations revealed by molecular dynamics simulations. Biophys J 2006;90:3908–18.10.1529/biophysj.105.075341Search in Google Scholar
8 Van der Kamp MW, Daggett V. Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding. J Mol Biol 2010;404: 732–48.10.1016/j.jmb.2010.09.060Search in Google Scholar
9 Meli M, Gasset M, Colombo G. Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target. PLoS ONE 2011;6:e19093.10.1371/journal.pone.0019093Search in Google Scholar
10 Billeter M, Wüthrich K. The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations. Arch Virol Suppl 2000:251–63.10.1007/978-3-7091-6308-5_24Search in Google Scholar
11 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;20:169–82.10.1016/S1093-3263(01)00117-6Search in Google Scholar
12 Shamsir MS, Dalby AR. One gene, two diseases and three conformations: molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures. Proteins 2005;59:275–90.10.1002/prot.20401Search in Google Scholar PubMed
13 Zhang J, Liu DD. Molecular dynamics studies on the structural stability of wild-type dog prion protein. J Biomol Struct Dyn 2011;28:861–9.10.1080/07391102.2011.10508613Search in Google Scholar PubMed
14 Castilla J, Gonzalez-Romero D, Saá P, Morales R, De Castro J, Soto C. Crossing the species barrier by PrP(Sc) replication in vitro generates unique infectious prions. Cell 2008;134: 757–68.10.1016/j.cell.2008.07.030Search in Google Scholar PubMed PubMed Central
15 Dong C-F, Shi S, Wang X-F, An R, Li P, Chen J-M, et al. The N-terminus of PrP is responsible for interacting with tubulin and fCJD related PrP mutants possess stronger inhibitive effect on microtubule assembly in vitro. Arch Biochem Biophys 2008;470:83–92.10.1016/j.abb.2007.11.007Search in Google Scholar PubMed
16 Turnbaugh JA, Westergard L, Unterberger U, Biasini E, Harris DA. The N-terminal, polybasic region is critical for prion protein neuroprotective activity. PLoS ONE 2011;6:e25675.10.1371/journal.pone.0025675Search in Google Scholar PubMed PubMed Central
17 Lashuel H, Overk C. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 2012;14:38–48.10.1038/nrn3406Search in Google Scholar PubMed PubMed Central
18 Hess B, Kutzner C, van der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 2008;4:435–47.10.1021/ct700301qSearch in Google Scholar PubMed
19 Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L. The FoldX web server: an online force field. Nucleic Acids Res 2005;33:W382–8.10.1093/nar/gki387Search in Google Scholar PubMed PubMed Central
20 Linding R, Jensen LJ, Diella F, Bork P, Gibson TJ, Russell RB. Protein disorder prediction: implications for structural proteomics. Structure 2003;11:1453–9.10.1016/j.str.2003.10.002Search in Google Scholar PubMed
21 Lysek DA, Schorn C, Nivon LG, Esteve-Moya V, Christen B, Calzolai L, et al. Prion protein NMR structures of cats, dogs, pigs, and sheep. Proc Natl Acad Sci USA 2005;102:640–5.10.1073/pnas.0408937102Search in Google Scholar PubMed PubMed Central
22 Vidal E, Fernández-Borges N, Pintado B, Ordóñez M, Márquez M, Fondevila D, et al. Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features. J Neurosci 2013;33:7778–86.10.1523/JNEUROSCI.0244-13.2013Search in Google Scholar PubMed PubMed Central
23 Zhang J. Studies on the structural stability of rabbit prion probed by molecular dynamics simulations of its wild-type and mutants. J Theor Biol Elsevier 2010;264:119–22.10.1016/j.jtbi.2010.01.024Search in Google Scholar PubMed
24 Wagoner VA, Cheon M, Chang I, Hall CK. Computer simulation study of amyloid fibril formation by palindromic sequences in prion peptides. Proteins 2011;1–14.10.1002/prot.23034Search in Google Scholar PubMed PubMed Central
25 Deleault NR, Harris BT, Rees JR, Supattapone S. Formation of native prions from minimal components in vitro. Proc Natl Acad Sci USA 2007;104:9741–6.10.1073/pnas.0702662104Search in Google Scholar PubMed PubMed Central
26 Taylor DR, Hooper NM. Role of lipid rafts in the processing of the pathogenic prion and Alzheimer’s amyloid-beta proteins. Semin Cell Dev Biol 2007;18:638–48.10.1016/j.semcdb.2007.07.008Search in Google Scholar PubMed
27 Pani A, Mandas A, Dessì S. Cholesterol, Alzheimer’s disease, prion disorders: a ménage à trois? Curr Drug Targets 2010;11:1018–31.10.2174/138945010791591386Search in Google Scholar PubMed
28 Klingenstein R, Lober S, Kujala P, Godsave S, Leliveld SR, Gmeiner P, et al. Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent-resistant membrane compartments. J Neurochem 2006;98:1696.10.1111/j.1471-4159.2006.04047.xSearch in Google Scholar
©2015 by De Gruyter