Role of D278N mutation for stability of prion dimer and tetramer structure

• Autorzy: Jurkowski W.

Identyfikatory

DOI

10.1515/bams-2015-0002

• Języki publikacji: EN

Abstrakty

EN

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. Proteinprotein 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 diseasecausing 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.

Słowa kluczowe

EN

molecular dynamics; population shift; prion disease; prion oligomerization

• Wydawca: Uniwersytet Jagielloński - Collegium Medicum ; Index Copernicus Sp. z o.o.
• Czasopismo: Bio-Algorithms and Med-Systems
• Rocznik: 2015
• Tom: Vol. 11, no. 1
• Strony: 19--24
• Opis fizyczny: Bibliogr. 28 poz., rys., wykr.

Twórcy

autor

Jurkowski W.

• Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 EschBelval, Luxembourg

Bibliografia

• 1 Aguzzi A, Calella AM. Prions: protein aggregation and infectious diseases. Physiol Rev 2009;89:1105–52.
• 2 Soto C, Satani N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol Med 2010;17:14–24.
• 3 Flechsig E, Weissmann C. The role of PrP in health and disease. Curr Mol Med 2004;4:337–53.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 Billeter M, Wüthrich K. The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations. Arch Virol Suppl 2000:251–63.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 22 Vidal E, Fernández-Borges N, Pintado B, Ordóńez 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.
• 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.
• 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.
• 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.
• 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.
• 27 Pani A, Mandas A, Dessě S. Cholesterol, Alzheimer’s disease, prion disorders: a ménage ŕ trois? Curr Drug Targets 2010;11:1018–31.
• 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.