2023
DOI: 10.1021/jasms.2c00379
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Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein

Abstract: Αlpha-synuclein (αS) is an intrinsically disordered protein which exhibits a high degree of conformational heterogeneity. In vivo, αS experiences various environments which cause adaptation of its structural ensemble. Divalent metal ions are prominent in synaptic terminals where αS is located and are thought to bind to the αS C-terminal region. Herein, we used native nanoelectrospray ionization ion mobility-mass spectrometry to investigate changes in the charge state distribution and collision cross sections o… Show more

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Cited by 13 publications
(13 citation statements)
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“…This also supports that the gaseous structures measured by ion mobility are thus largely governed by gas-phase electrostatics, not kinetically trapped solution states. However, though cases where the CSD of αSN was observed as a bimodal or multimodal distribution were indicative of the presence of a more compact conformational subfamily; 26,28,33 we observed no evidence of a second distribution under our experimental conditions.…”
Section: Resultscontrasting
confidence: 65%
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“…This also supports that the gaseous structures measured by ion mobility are thus largely governed by gas-phase electrostatics, not kinetically trapped solution states. However, though cases where the CSD of αSN was observed as a bimodal or multimodal distribution were indicative of the presence of a more compact conformational subfamily; 26,28,33 we observed no evidence of a second distribution under our experimental conditions.…”
Section: Resultscontrasting
confidence: 65%
“…Though the +8 ions follow well-understood "compaction" mechanisms, it is clear that some of the highly charged ions explore a huge range of conformations in the gas phase, including the formation of new intramolecular interactions that have not been identified for αSN with solution measurements. 32,46,61 Therefore, while the CCS distributions are accurate descriptors of the relative order or disorder of proteins 11 and reflect changes in solution conformational space upon change in solution conditions 24 or ligand/metal binding, [25][26][27][28] the structural features of the conformers themselves may not reflect the solution conformers.…”
Section: Comparison Of Sra Gp Representative Conformers To Nmr and Id...mentioning
confidence: 99%
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“…Peptide IHIHIQI was the most active sequence and has served as template to develop many other catalytic amyloids. ,, Amyloid activities include hydrolysis of ester and phosphoester bonds, redox reactions, and retro aldol condensations, among others. , Based on the active site of nucleotide-processing enzymes, we have developed catalytic amyloids carrying active aspartate groups (Asp). , These catalytic amyloids exhibit manganese-dependent hydrolytic activity that specifically cleaves the phosphoanhydride bonds of adenosine triphosphate (ATP) and other nucleotides. Most catalytic amyloids rely on metal ions for their activity. , It is known that divalent metals can influence the aggregation of different (noncatalytic) pathological amyloids. Herein, we show that biologically relevant metal ions can guide the assembly of a small peptide into metal-specific aggregation kinetics and morphologies. All tested ions triggered the conformational transition to the amyloid state, but only manganese induced hydrolytic activity.…”
Section: Introductionmentioning
confidence: 88%
“…Post-translational modifications (PTMs) such as N-terminal acetylation have been reported to decrease the rate of α-syn aggregation, whereas phosphorylation at Ser-129 has been correlated with increased α-syn aggregation . The binding of metal ions such as copper, manganese, and zinc have been linked to increased aggregation of α-syn. A shift in α-syn aggregation due to modifications is well documented.…”
Section: Introductionmentioning
confidence: 99%