Abstract
Amyloid proteins, the major component of the fibrillar plaques and tangles in neurodegenerative diseases,1 are often intrinsically disordered in solution. Amyloid-beta is the prototypical peptide from Alzheimer's disease. We demonstrated that even for this fast-aggregating peptide, the aggregation process can be monitored by spin-label mobility, determined by continuous wave EPR.2 Here we show that membrane-mimicking detergents reduce aggregate size, and above the critical micelle concentration promote monomeric amyloid-beta.Membrane interaction of alpha-synuclein, the protein related to Parkinson's disease, may be physiologically relevant.3 The structure of the vesicle-bound form of this protein is therefore of interest. Binding strength and mode of interaction depend strongly on membrane composition,4 and long-distance constraints from EPR are particularly useful to determine membrane-bound conformations.5 Here we focus on the relation of membrane-related aggregation6 and fibril structure.7 Comparing the arrangement of alpha-synuclein in both forms we speculate that membrane aggregation observed by double electron electron resonance (DEER or PELDOR) on POPG-SUV's6 is off-pathway for fibrillization.References1 F.Chiti and C.M.Dobson. Annu. Rev. Biochem., 75, (2006) 333-366; N.Yamamoto, et al. J. Neurochem., 90, (2004) 62-69.; V.Rangachari, et al. Biochemistry., 46, (2007) 12451-12462; B.O'Nuallain, et al. J. Neurosci., 30, (2010) 14411-14419. 2 I.Sepkhanova, et al. Applied Magnetic Resonance., 36, (2009) 209-222. 3I. Dikiy and D. Eliezer, Biochimica et Biophysica Acta-Biomembranes., 1818(4), 1013 (2012).4 M. Drescher, M. Huber, and V. Subramaniam, Chembiochem. 13(6), 761 (2012), and refs therein. 5J.N.Rao, C.C.Jao, B.G.Hegde, R.Langen, and T.S.Ulmer. Journal of the American Chemical Society., 2010, 132, 8657-8668. 6 M. Drescher, et al., 132(12), 4080-4082 (2010). 7M. Hashemi Shabestari, et al., Biophys. J. 102 ed.2012), p.454a.
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