Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

被引：84

作者：

Viennet, Thibault ^{[1
,2
]}

Woerdehoff, Michael M. ^{[1
]}

Uluca, Boran ^{[1
,2
]}

Poojari, Chetan ^{[2
,3
,4
]}

Shaykhalishahi, Hamed ^{[1
]}

Willbold, Dieter ^{[1
,2
]}

Strodel, Birgit ^{[2
]}

Heise, Henrike ^{[1
,2
]}

Buell, Alexander K. ^{[1
]}

Hoyer, Wolfgang ^{[1
,2
]}

Etzkorn, Manuel ^{[1
,2
]}

机构：

[1] Heinrich Heine Univ, Inst Phys Biol, Univ Str, D-40225 Dusseldorf, Germany

[2] Forschungszentrum Julich, Inst Complex Syst ICS 6, Wilhelm Johnen Str, D-52428 Julich, Germany

[3] Tampere Univ Technol, Dept Phys, Korkeakoulunkatu 10, Tampere 33720, Finland

[4] Univ Helsinki, Dept Phys, Gustaf Hallstromin katu 2a, Helsinki 00560, Finland

来源：

COMMUNICATIONS BIOLOGY | 2018年 / 1卷

关键词：

N-TERMINAL ACETYLATION; PARTICLE MESH EWALD; PHOSPHOLIPID-BINDING; HIGHLY EFFICIENT; NMR; PROTEIN; AGGREGATION; DYNAMICS; SIMULATIONS; VESICLES;

D O I：

10.1038/s42003-018-0049-z

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The protein alpha-Synuclein (alpha S) is linked to Parkinson's disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of alpha S. Following previous studies using micelles and vesicles, we present a comprehensive study of alpha S interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize alpha S interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific alpha S membrane affinities, and determine modulations of alpha S membrane binding due to alpha S acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for alpha S amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.

引用

页数：12