Electrostatic and hydrophobic interactions of lipid-associated α-synuclein: The role of a water-limited interfaces in amyloid fibrillation

Choi, Tae Su; Han, Jong Yoon; Heo, Chae Eun; Lee, Sun Woo; Kim, Hugh I.

doi:10.1016/j.bbamem.2018.02.007

Cited by 13 publications

(11 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This agrees with the previous report that the N-terminal fragment of apoA-I is embedded in proximity to the interfacial region on PC membranes [59]. In addition, it was reported that SM has no noticeable effects on membrane-catalyzed fibril formation of IAPP [30,34] because IAPP interacts with the headgroup region and does not penetrate into the acyl chain region to form amyloid fibrils [60,61]. The reason why the formation of stable α-helix structure in the presence of SM (Fig.…”

Section: Author Manuscriptsupporting

confidence: 92%

Phosphatidylethanolamine accelerates aggregation of the amyloidogenic N‐terminal fragment of apoA‐I

et al. 2020

View full text Add to dashboard Cite

Membrane lipid composition is known to influence aggregation and fibril formation of many amyloidogenic proteins. Here, we found that phosphatidylethanolamine (PE) accelerates aggregation of the N-terminal 1-83 fragment of an amyloidogenic G26R variant of apoA-I on lipid membranes. Circular dichroism and isothermal titration calorimetry measurements demonstrated that PE does not affect the α-helical structure and lipid binding property of apoA-I 1-83/G26R. Rather, fluorescence measurements indicated that PE induces more ordered lipid packing at the interfacial and acyl chain regions, providing more hydrophobic environments especially around the highly amyloidogenic regions in apoA-I on the membrane surface. These results suggest that PE promotes aggregation of the amyloidogenic N-terminal fragment of apoA-I on lipid membranes by inducing hydrophobic membrane environments.

show abstract

Section: Author Manuscriptsupporting

confidence: 92%

Phosphatidylethanolamine accelerates aggregation of the amyloidogenic N‐terminal fragment of apoA‐I

et al. 2020

View full text Add to dashboard Cite

show abstract

“…This enables the rest of the protein to form an amphipathic α-helix embedded in the headgroup layer of the vesicles [ 9 , 48 ]. The α-helical part contains multiple lysine residues found in the N-terminal region [ 9 , 55 ], with 7 imperfect 11-residue repeats of KTKEGV sequence (58), similar to those found in apolipoproteins [ 6 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…When associated to anionic phospholipid vesicles α-syn forms a linear helix [ 50 ]. The interactions between α-syn and membranes have been found to modulate the α-syn fibril formation pathway, likely through triggering heterogeneous primary nucleation [ 8 , 20 , 24 , 25 , [51] , [52] , [53] , [54] , [55] ].…”

Section: Introductionmentioning

confidence: 99%

Ganglioside lipids accelerate α-synuclein amyloid formation

Gaspar

Pallbo

Weininger

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

The deposition of α-synuclein fibrils is one hallmark of Parkinson's disease. Here, we investigate how ganglioside lipids, present in high amounts in neurons and exosomes, influence the aggregation kinetics of α-synuclein. Gangliosides, as well as, other anionic lipid species with small or large headgroups were found to induce conformational changes of α-synuclein monomers and catalyse their aggregation at mildly acidic conditions. Although the extent of this catalytic effect was slightly higher for gangliosides, the results imply that charge interactions are more important than headgroup chemistry in triggering aggregation. In support of this idea, uncharged lipids with large headgroups were not found to induce any conformational change and only weakly catalyse aggregation. Intriguingly, aggregation was also triggered by free ganglioside headgroups, while these caused no conformational change of α-synuclein monomers. Our data reveal that partially folded α-synuclein helical intermediates are not required species in triggering of α-synuclein aggregation.

show abstract

“…Due to the polybasic nature of its N-terminal membrane binding domain, α-Syn is known to exhibit high affinity for phospholipids with an anionic head group, particularly PS. 47,48 Here we found that in bilayers without DHA, residues ∼15−30 of α-Syn 100 residing in the lipid head group region, have preference for interactions with anionic POPS lipids (Figure S5). Particularly the basic Lys (K) residues K10, K21, K23, K32, K43, and K45 undergo strong electrostatic interactions with PS lipid head groups (Figure 6c), whereas the first ∼15 N-terminal residues, which penetrated into the hydrocarbon region, show the strongest affinity to interact with POPE lipids (Figure S5).…”

Section: ■ Resultsmentioning

confidence: 80%

Polyunsaturated Fatty Acid Modulates Membrane-Bound Monomeric α-Synuclein by Modulating Membrane Microenvironment through Preferential Interactions

Manna

Murarka

2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

There is ample evidence that both native functions and pathogenic aggregation of α-synuclein are intimately dependent on lipid interactions and fatty acid type; the regulatory mechanism however remains unclear. In the present work, using extensive atomistic molecular dynamics simulations and enhancedsampling, we have focused on exploring the mechanism of fatty acid dependent regulation of monomeric α-Syn 100 in a native synaptic vesicle-like membrane. Our results show that α-Syn 100 spontaneously binds to the membrane through its N-terminal region (residues 1−34), where the depth of membrane insertion, the structure, and orientation of the membrane-bound α-Syn 100 and its impact on membrane structure are modulated by docosahexaenoic acid (DHA). DHA is a polyunsaturated fatty acid abundantly found in the brain and known to promote the oligomerization of α-synuclein. We found that DHA exhibits marked propensity to interact with monomeric α-Syn 100 and modulates the microenvironment of the protein by preferentially sorting DHAcontaining phospholipids, depleting other phospholipids and cholesterol as well as increasing the proportion of anionic to neutral lipids in the immediate vicinity of the protein. Owing to the unique conformational flexibility, DHA chains form more lipid-packing defects in the membrane and efficiently coat the membrane-embedded surface of the protein, compared to the saturated and monounsaturated fatty acids. DHA thus makes the bilayer more amiable to protein adsorption and less prone to α-synuclein-induced perturbation associated with cytotoxicity. Indeed, in the absence of DHA, we observed significant thinning of the local bilayer membrane induced by α-Syn 100 . Though α-Syn 100 is predominantly α-helical in membranes studied here, in the presence of DHA we observe formation of β-sheet/β-strands in the C-terminal region (residues 35−100) of α-Syn 100 , which is extended out from the membrane surface. Notably, DHA induces β structure in the NAC domain of α-Syn 100 and promotes extended conformations as well as large solvent exposure of this hydrophobic domain, properties that are known to facilitate self-assembly of α-synuclein. To the best of our knowledge, this study for the first time provides the atomistic insights into DHA-induced regulatory mechanism of monomeric α-synuclein, having implications in protein structure and its physiological/pathological functions.

show abstract

Electrostatic and hydrophobic interactions of lipid-associated α-synuclein: The role of a water-limited interfaces in amyloid fibrillation

Cited by 13 publications

References 145 publications

Phosphatidylethanolamine accelerates aggregation of the amyloidogenic N‐terminal fragment of apoA‐I

Phosphatidylethanolamine accelerates aggregation of the amyloidogenic N‐terminal fragment of apoA‐I

Ganglioside lipids accelerate α-synuclein amyloid formation

Polyunsaturated Fatty Acid Modulates Membrane-Bound Monomeric α-Synuclein by Modulating Membrane Microenvironment through Preferential Interactions

Contact Info

Product

Resources

About