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Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes

1998; Elsevier BV; Volume: 273; Issue: 16 Linguagem: Inglês

10.1074/jbc.273.16.9443

1083-351X

W. Sean Davidson, Ana Jonas, David F. Clayton, Julia M. George,

Cellular transport and secretion

α-Synuclein is a highly conserved presynaptic protein of unknown function. A mutation in the protein has been causally linked to Parkinson's disease in humans, and the normal protein is an abundant component of the intraneuronal inclusions (Lewy bodies) characteristic of the disease. α-Synuclein is also the precursor to an intrinsic component of extracellular plaques in Alzheimer's disease. The α-synuclein sequence is largely composed of degenerate 11-residue repeats reminiscent of the amphipathic α-helical domains of the exchangeable apolipoproteins. We hypothesized that α-synuclein should associate with phospholipid bilayers and that this lipid association should stabilize an α-helical secondary structure in the protein. We report that α-synuclein binds to small unilamellar phospholipid vesicles containing acidic phospholipids, but not to vesicles with a net neutral charge. We further show that the protein associates preferentially with vesicles of smaller diameter (20–25 nm) as opposed to larger (∼125 nm) vesicles. Lipid binding is accompanied by an increase in α-helicity from 3% to approximately 80%. These observations are consistent with a role in vesicle function at the presynaptic terminal.