JBPC  Vol.2 No.2 , May 2011
Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation
ABSTRACT
Aggregation of alpha-synuclein leads to the formation of Lewy bodies in the brains of patients affected by Parkinson's disease (PD). Native human alpha-synuclein is unfolded in solution but assumes a partial alpha-helical conformation upon transient binding to lipid membranes. Annealing Molecular Dynamics (AMD) was used to generate a diverse set of unfolded conformers of free monomeric wild-type alpha-synuclein and PD-associated mutants A30P and A53T. The AMD conformers were compared in terms of secondary structure, hydrogen bond network, solvent-accessible surface per residue, and molecular volume. The objective of these simulations was to identify structural properties near mutation sites and the non-amyloid component (NAC) region that differ between wild- type and disease-associated variants and may be associated to aggregation of alpha- synuclein. Based on experimental evidence, a hypothesis exists that aggregation involves the formation of intermolecular beta sheets. According to our results, disease-associated mutants of alpha-synuclein are no more propense to contain extended beta regions than wild-type alpha-synuclein. Moreover, extended beta structures (necessary for beta sheet formation) were not found at or around positions 30 and 53, or the NAC region in any unfolded conformer of wild-type, A30P or A53T alpha-synuclein, under the conditions of the simulations. These results do not support the hypothesis that the mutant's higher propensity to aggregation results solely from changes in amino acid sequence leading to changes in secondary structure folding propensity.

Cite this paper
nullBalesh, D. , Ramjan, Z. and Floriano, W. (2011) Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation. Journal of Biophysical Chemistry, 2, 124-134. doi: 10.4236/jbpc.2011.22015.
References
[1]   Clayton, D.F. and George, J.M. (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. Journal of Neuroscience Research, 58, 120-129. doi:10.1002/(SICI)1097-4547(19991001)58:1<120::AID-JNR12>3.0.CO;2-E

[2]   Bueler, H. (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Experimental Neurology, 218, 235-246.

[3]   Zhou, H.Y. and Chen, S.D. (2005) Parkin, Parkin substrates and Parkinson's disease. Progress in Biochemistry and Biophysics, 32, 912-916.

[4]   Dekker, M.C.J. et al. (2003) Parkinson’s disease: Piecing together a genetic jigsaw. Brain, 126, 1722-1733. doi:10.1093/brain/awg172

[5]   Hattori, N. et al. (2000) Autosomal recessive juvenile parkinsonism: A key to understanding nigral dege- neration in sporadic Parkinson’s disease. Neuropathology, 20, S85-S90. doi:10.1046/j.1440-1789.2000.00312.x

[6]   Wszolek, Z.K. and Markopoulou, K. (1999) Molecular genetics of familial parkinsonism. Parkinsonism & Related Disorders, 5, 145-155. doi:10.1016/S1353-8020(99)00030-9

[7]   Schapira, A.H.V. (1997) Pathogenesis of Parkinson’s disease. Baillieres Clinical Neurology, 6, 15-36.

[8]   Spillantini, M.G. et al. (1997) Alpha-synuclein in Lewy bodies. Nature, 388, 839-840. doi:10.1038/42166

[9]   Sit, S.Y. (2000) Dopamine agonists in the treatment of Parkinson’s disease—Past, present and future. Current Pharmaceutical Design, 6, 1211-1248. doi:10.2174/1381612003399581

[10]   Khan, A. et al. (2005) Metals accelerate the formation and direct the structure of amyloid fibrils of NAC. Journal of Inorganic Biochemistry, 99, 1920-1927. doi:10.1016/j.jinorgbio.2005.06.018

[11]   Lashuel, H.A. et al. (2000) Protofilaments, filaments, ribbons, and fibrils from peptidomimetic self-assembly: Implications for amyloid fibril formation and materials science. Journal of the American Chemical Society, 122, 5262-5277. doi:10.1021/ja9937831

[12]   Jellinger, K.A. (2007) Morphological substrates of parkinsonism with and without dementia: A retrospective clinico-pathological study. Journal of Neural Transmission-Supplement, 72, 91-104.

[13]   Cabedo, N. et al. (2009) An overview on benzylisoquinoline derivatives with dopaminergic and serotonergic activities. Current Medicinal Chemistry, 16, 2441-2467. doi:10.2174/092986709788682100

[14]   Montastruc, J.L. et al. (1999) Treatment of Parkinson’s disease should begin with a dopamine agonist. Movement Disorders, 14, 725-730. doi:10.1002/1531-8257(199909)14:5<725::AID-MDS1003>3.0.CO;2-L

[15]   Gottwald, M.D. et al. (1997) New pharmacotherapy for Parkinson’s disease. Annals of Pharmacotherapy, 31, 1205-1217.

[16]   Uitti, R.J. and Ahlskog, J.E. (1996) Comparative review of dopamine receptor agonists in Parkinson's disease. Cns Drugs, 5, 369-388. doi:10.2165/00023210-199605050-00006

[17]   Tofaris, G.K. and Spillantini, M.G. (2007) Physiological and pathological properties of alpha-synuclein. Cellular and Molecular Life Sciences, 64, 2194-2201. doi:10.1007/s00018-007-7217-5

[18]   Ulmer, T.S. et al. (2005) Structure and dynamics of micelle-bound human alpha-synuclein. Journal of Biological Chemistry, 280, 9595-9603. doi:10.1074/jbc.M411805200

[19]   Dedmon, M.M. et al. (2005) Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations. Journal of the American Chemical Society, 127, 476-477. doi:10.1021/ja044834j

[20]   Bertoncini, C.W. et al. (2005) Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation. Journal of Biological Chemistry, 280, 30649-30652. doi:10.1074/jbc.C500288200

[21]   I.F. Tsigelny, et al. (2007) Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS Journal, 274, 1862-1877. doi:10.1111/j.1742-4658.2007.05733.x

[22]   Krieger, E. et al. (2004) Making optimal use of empirical energy functions: Force-field parameterization in crystal space. Proteins, 57, 678-683. doi:10.1002/prot.20251

[23]   Kabsch, W. and Sander, C. (1983) Dictionary of protein secondary structure: Pattern recognition of hydro- gen-bonded and geometrical features. Biopolymers, 22, 2577-2637. doi:10.1002/bip.360221211

[24]   Krieger, E. et al. (2002) Increasing the precision of comparative models with YASARA NOVA—A self-parameterizing force field. Proteins, 47, 393-402. doi:10.1002/prot.10104

[25]   Uversky, V.N. et al. (2001) Evidence for a partially folded intermediate in alpha-synuclein fibril formation. Journal of Biological Chemistry, 276, 10737-10744. doi:10.1074/jbc.M010907200

[26]   Neal, S. et al. (2003) Rapid and accurate calculation of protein H-1, C-13 and N-15 chemical shifts. Journal of Biomolecular Nmr, 26, 215-240. doi:10.1023/A:1023812930288

[27]   Bodner, C.R. et al. (2010) Differential phospholipid binding of alpha-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biochemistry, 49, 862-871. doi:10.1021/bi901723p

[28]   Chandra, S. et al. (2003) A broken alpha-helix in folded alpha-synuclein. Journal of Biological Chemistry, 278, 15313-15318. doi:10.1074/jbc.M213128200

[29]   Fernandez, C.O. et al. (2004) NMR of alpha- synuclein-polyamine complexes elucidates the me- chanism and kinetics of induced aggregation. Embo Journal, 23, 2039-2046.

[30]   Georgieva, E.R. et al. (2010) The Lipid-binding Domain of Wild Type and Mutant alpha-Synuclein compactness and interconversion between the broken and extended helix forms. Journal of Biological Chemistry, 285, 28261-28274. doi:10.1038/sj.emboj.7600211

[31]   Sasakawa, H. et al. (2007) Ultra-high field NMR studies of antibody binding and site-specific phosphorylation of alpha-synuclein. Biochemical and Biophysical Research Communications, 363, 795-799. doi:10.1016/j.bbrc.2007.09.048

[32]   Wu, K.P. et al. (2008) Characterization of conforma- tional and dynamic properties of natively unfolded human and mouse alpha-synuclein ensembles by NMR: Implication for aggregation. Journal of Molecular Biology, 378, 1104-1115. doi:10.1016/j.jmb.2008.03.017

[33]   Wolozin, B. and Golts, N. (2002) Iron and Parkinson’s disease. Neuroscientist, 8, 22-32. doi:10.1177/107385840200800107

[34]   Golts, N. et al. (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. Journal of Biological Chemistry, 277, 16116-16123. doi:10.1074/jbc.M107866200

[35]   Rasia, R.M. et al. (2005) Structural characterization of copper(II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson’s disease. Proceedings of National Academy Sciences of U.S.A., 102, 4294-4299. doi:10.1073/pnas.0407881102

[36]   Latawiec, D. et al. (2010) Modulation of alpha-synuclein aggregation by dopamine analogs. Plos One, 5, e9234. doi:10.1371/journal.pone.0009234

[37]   Gatto, N.et al. (2009) Alpha-Synuclein repeat polymorphisms and pesticide exposure in Parkinson's disease. Epidemiology, 20, S124-S124. doi:10.1097/01.ede.0000362429.51721.26

[38]   Betarbet, R. et al. (2006) Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Neurobiology of Disease, 22, 404-420. doi:10.1016/j.nbd.2005.12.003

[39]   Cicchetti, F. et al. (2009) Environmental toxins and Parkinson's disease: What have we learned from pesticide-induced animal models? Trends in Phar- macological Sciences, 30, 475-483. doi:10.1016/j.tips.2009.06.005

[40]   Richardson, J.R. et al. (2009) Elevated Serum Pesticide Levels and Risk of Parkinson Disease. Archives of Neurology, 66, 870-875. doi:10.1001/archneurol.2009.89

[41]   Yoon, J. et al. (2009) Simulation studies on the stabilities of aggregates formed by fibril-forming segments of alpha-Synuclein. Journal Biomolecular Structure and Dynamics, 27, 259-270.

 
 
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