期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 44, 页码 34393-34398出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M004851200
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资金
- NIA NIH HHS [1R01 AG13762] Funding Source: Medline
- NIGMS NIH HHS [5T32GM07143-20] Funding Source: Medline
alpha -Synuclein has been centrally implicated in neurodegenerative disease, and a normal function in developmental synaptic plasticity has been suggested by studies in songbirds. A variety of observations suggest the protein partitions between membrane and cytosol, a behavior apparently conferred by a conserved structural similarity to the exchangeable apolipoproteins. Here we show that the capacity to bind lipids is broadly distributed across exons 3, 4, and 5 (encoding residues 1-102), Binding to phosphatidylserine-containing vesicles requires the presence of all three exons, while binding to phosphatidic acid can be mediated by any one of the three. Consistent with a class A2 helical binding mechanism, lipid association is disrupted by introduction of charged residues along the hydrophobic face of the predicted cu-helix and also by biotinylation of conserved lysines (which line the interfacial region). Circular dichroism spectroscopy reveals a general correlation between the amount of lipid-induced alpha -helix content and the degree of binding to PS-containing vesicles. Two point mutations associated with Parkinson's disease have little (A30P) or no (A53T) effect on lipid binding or a-helicity. These results are consistent with the hypothesis that alpha -synuclein's normal functions depend on an ability to undergo a large conformational change in the presence of specific phospholipids.
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