Inhibition of α-Synuclein Fibrillization by Dopamine Is Mediated by Interactions with Five C-Terminal Residues and with E83 in the NAC Region

Herrera, Fernando E.; Chesi, Alessandra; Paleologou, Katerina E.; Schmid, Adrien W.; Muñoz, Adriana; Vendruscolo, Michele; Gustincich, Stefano; Lashuel, Hilal A.; Carloni, Paolo

doi:10.1371/journal.pone.0003394

Cited by 110 publications

(142 citation statements)

References 66 publications

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“…The DA binding site was located in the C-terminal amino acids 127 MPSEE 131 . Indeed binding of DA to AS has been reported near the 125 YEMPS 129 region 59 , which overlaps with the binding site observed by topdown ETD. The localization of M 127 within this region is interesting as it might explain the mechanism by which DA prevents fibril formation and induces DA-dependent oligomerization.…”

Section: Da Binding Is Observed Preferentially With As In Partially Esupporting

confidence: 70%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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The intrinsically disordered and amyloidogenic protein -synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nano-electrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein-ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as e.g. oxidation.

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Section: Da Binding Is Observed Preferentially With As In Partially Esupporting

confidence: 70%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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“…A variety of aromatic molecules such as EGCG [31,50,51], baicalein [52], dopamine [53][54][55], other polyphenols [56], thioflavins [57], curcumin [58][59][60], an anti-PD drug selengiline [61], b-hairpins [62] and many other compounds [63,64] induced formation of mostly disordered a-synuclein oligomers, although in some cases [52] the residual b-structure was found. Many of these compounds were preferentially bound to the C-terminus of a-synuclein [31,62,65]. Addition of EGCG to the preformed b-sheet-rich oligomers did not lead to their disaggregation or loss of secondary structure but did inhibit their interaction with membranes [51].…”

Section: A-synuclein Oligomersmentioning

confidence: 99%

Structural, morphological, and functional diversity of amyloid oligomers

2015

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a b s t r a c tProtein misfolding and aggregation are known to play a crucial role in a number of important human diseases (Alzheimer's, Parkinson's, prion, diabetes, cataracts, etc.) as well as in a multitude of physiological processes. Protein aggregation is a highly complex process resulting in a variety of aggregates with different structures and morphologies. Oligomeric protein aggregates (amyloid oligomers) are formed as both intermediates and final products of the aggregation process. They are believed to play an important role in many protein aggregation-related diseases, and many of them are highly cytotoxic. Due to their instability and structural heterogeneity, information about structure, mechanism of formation, and physiological effects of amyloid oligomers is sparse. This review attempts to summarize the existing information on the major properties of amyloid oligomers.

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“…Dopamine has previously been shown to inhibit α-Syn fibrillation when used at equimolar ratios. 51 This is thought to occur through hydrophobic interactions with the C-terminus of the protein preventing the formation of mature α-Syn fibrils. However, it was shown that co-incubation of α-Syn with dopamine may give rise to small pre-fibrillar oligomers.…”

Section: A Possible Mechanism Of Toxicitymentioning

confidence: 99%

Mechanism of Membrane Interaction and Disruption by α-Synuclein

et al. 2011

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Parkinson's disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein -synuclein. There is increasing evidence suggesting that the aggregation of -synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface-sensitive imaging technique supercritical angle fluorescence microscopy and Förster resonance energy transfer, we report the direct observation of -synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of -synuclein studied, namely, the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing -synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross--sheet aggregates and damaged the membrane at submicromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble part of the yet poorly understood cellular toxicity phenomenon in vivo. AbstractParkinson`s disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein α-Synuclein. There is increasing evidence suggesting that the aggregation of α−Synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface sensitive imaging technique super critical angle fluorescence microscopy and Förster resonance energy transfer we report the direct observation of α−Synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of α−Synuclein studied, namely the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing α−Synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross β-sheet aggregates and damaged the membrane at sub-micromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble the yet poorly...

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Inhibition of α-Synuclein Fibrillization by Dopamine Is Mediated by Interactions with Five C-Terminal Residues and with E83 in the NAC Region

Cited by 110 publications

References 66 publications

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Structural, morphological, and functional diversity of amyloid oligomers

Mechanism of Membrane Interaction and Disruption by α-Synuclein

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