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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Phosphatidylserines
Apolipoprotein A-I
Cholesterol
Membranes
Lipids
Fluorescence
Unilamellar Liposomes
Fluidity
Calorimetry
Cell membranes
Coulomb interactions
Titration
Amyloid
Conformations
Assays
Nucleation
Stabilization
Tissue
Amino Acids
Peptides

ASJC Scopus subject areas

  • General

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Effect of phosphatidylserine and cholesterol on membrane-mediated fibril formation by the N-terminal amyloidogenic fragment of apolipoprotein A-I. / Mizuguchi, Chiharu; Nakamura, Mitsuki; Kurimitsu, Naoko; Ohgita, Takashi; Nishitsuji, Kazuchika; Baba, Teruhiko; Shigenaga, Akira; Shimanouchi, Toshinori; Okuhira, Keiichiro; Otaka, Akira; Saito, Hiroyuki.

In: Scientific Reports, Vol. 8, No. 1, 5497, 01.12.2018.

Research output: Contribution to journalArticle

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, vol. 8, no. 1, 5497. https://doi.org/10.1038/s41598-018-23920-3
Mizuguchi, Chiharu ; Nakamura, Mitsuki ; Kurimitsu, Naoko ; Ohgita, Takashi ; Nishitsuji, Kazuchika ; Baba, Teruhiko ; Shigenaga, Akira ; Shimanouchi, Toshinori ; Okuhira, Keiichiro ; Otaka, Akira ; Saito, Hiroyuki. / Effect of phosphatidylserine and cholesterol on membrane-mediated fibril formation by the N-terminal amyloidogenic fragment of apolipoprotein A-I. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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