Journal of Biological Chemistry
Volume 280, Issue 36, 9 September 2005, Pages 31664-31672
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Lipids and Lipoproteins
A Combinatorial Code for the Interaction of α-Synuclein with Membranes*

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Considerable genetic and pathological evidence has implicated the small, soluble protein α-synuclein in the pathogenesis of familial and sporadic forms of Parkinsons disease (PD). However, the precise role of α-synuclein in the disease process as well as its normal function remain poorly understood. We recently found that an interaction with lipid rafts is crucial for the normal, pre-synaptic localization of α-synuclein. To understand how α-synuclein interacts with lipid rafts, we have now developed an in vitro binding assay to rafts purified from native membranes. Recapitulating the specificity observed in vivo, recombinant wild type but not PD-associated A30P mutant α-synuclein binds to lipid rafts isolated from cultured cells and purified synaptic vesicles. Proteolytic digestion of the rafts does not disrupt the binding of α-synuclein, indicating an interaction with lipid rather than protein components of these membranes. We have also found that α-synuclein binds directly to artificial membranes whose lipid composition mimics that of lipid rafts. The binding of α-synuclein to these raft-like liposomes requires acidic phospholipids, with a preference for phosphatidylserine (PS). Interestingly, a variety of synthetic PS with defined acyl chains do not support binding when used individually. Rather, the interaction with α-synuclein requires a combination of PS with oleic (18:1) and polyunsaturated (either 20:4 or 22:6) fatty acyl chains, suggesting a role for phase separation within the membrane. Furthermore, α-synuclein binds with higher affinity to artificial membranes with the PS head group on the polyunsaturated fatty acyl chain rather than on the oleoyl side chain, indicating a stringent combinatorial code for the interaction of α-synuclein with membranes.

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This work was supported by an Eli Lilly Japan Fellowship (to S.K.), a University of California, San Francisco Medical Scientist Training Program National Institutes of Health grant (to V. M. N.), a Society for Neuroscience Minority Fellowship (to M. D. A.), the Hillblom Foundation (to D. L. F.), the Sandler Neurogenetics Program and the Valley Foundation (to R. H. E.), and National Institutes of Health National Center for Research Resources Grant RR014606 to the UCSF Mass Spectrometry Facility. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.