Effect of phosphatidylserine and cholesterol on membrane-mediated fibril formation by the N-terminal amyloidogenic fragment of apolipoprotein A-I

Chiharu Mizuguchi, Mitsuki Nakamura, Naoko Kurimitsu, Takashi Ohgita, Kazuchika Nishitsuji, Teruhiko Baba, Akira Shigenaga, Toshinori Shimanouchi, Keiichiro Okuhira, Akira Otaka, Hiroyuki Saito

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Abstract

Here, we examined the effects of phosphatidylserine (PS) and cholesterol on the fibril-forming properties of the N-terminal 1-83 fragment of an amyloidogenic G26R variant of apoA-I bound to small unilamellar vesicles. A thioflavin T fluorescence assay together with microscopic observations showed that PS significantly retards the nucleation step in fibril formation by apoA-I 1-83/G26R, whereas cholesterol slightly enhances fibril formation. Circular dichroism analyses demonstrated that PS facilitates a structural transition from random coil to α-helix in apoA-I 1-83/G26R with great stabilization of the α-helical structure upon lipid binding. Isothermal titration calorimetry measurements revealed that PS induces a marked increase in capacity for binding of apoA-I 1-83/G26R to the membrane surface, perhaps due to electrostatic interactions of positively charged amino acids in apoA-I with PS. Such effects of PS to enhance lipid interactions and inhibit fibril formation of apoA-I were also observed for the amyloidogenic region-containing apoA-I 8-33/G26R peptide. Fluorescence measurements using environment-sensitive probes indicated that PS induces a more solvent-exposed, membrane-bound conformation in the amyloidogenic region of apoA-I without affecting membrane fluidity. Since cell membranes have highly heterogeneous lipid compositions, our findings may provide a molecular basis for the preferential deposition of apoA-I amyloid fibrils in tissues and organs.

Original languageEnglish
Article number5497
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Mizuguchi, C., Nakamura, M., Kurimitsu, N., Ohgita, T., Nishitsuji, K., Baba, T., Shigenaga, A., Shimanouchi, T., Okuhira, K., Otaka, A., & Saito, H. (2018). Effect of phosphatidylserine and cholesterol on membrane-mediated fibril formation by the N-terminal amyloidogenic fragment of apolipoprotein A-I. Scientific Reports, 8(1), [5497]. https://doi.org/10.1038/s41598-018-23920-3