Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

Mane, Jonathan Y.; Stepanova, Maria

doi:10.1002/2211-5463.12069

Cited by 17 publications

(28 citation statements)

References 73 publications

(176 reference statements)

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“…Further studies are required to further clarify which cluster might promote dimer formation. Previous simulations suggested that the β-strand-rich hydrophobic NAC segment is important for dimerization 1 . Since the centroid structure of cluster 1 has an exposed hydrophobic β-sheet that is extended, cluster 1 might be the potential structural subpopulation that promotes dimerization (Fig.…”

Section: Discussionmentioning

confidence: 98%

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The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Chen

Zaer

Drori

et al. 2020

Preprint

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The intrinsically disordered protein, α-synuclein, implicated in synaptic vesicle homeostasis and neurotransmitter release, is also associated with several neurodegenerative diseases. The different roles of α-synuclein are characterized by distinct structural states (membrane-bound, dimer, tetramer, oligomer, and fibril), which are originated from its various monomeric conformations. The pathological states, determined by the ensemble of α-synuclein monomer conformations and dynamic pathways of interconversion between dominant states, remain elusive due to their transient nature. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.

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Section: Discussionmentioning

confidence: 98%

“…α-Synuclein (α-syn) is a 140-residue protein containing an N-terminal segment (residues 1~60), a hydrophobic non-amyloid-β component (NAC) segment (residues 61~95), and an acidic C-terminal segment (residues 96~140) 1 . It is encoded by the SNCA gene in humans and is mainly expressed in the presynaptic terminals of neurons 2 .…”

Section: Introductionmentioning

confidence: 99%

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Chen

Zaer

Drori

et al. 2020

Preprint

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“…In another study, the effect of TMAO on unfolded α-synuclein was studied and observed that TMAO caused folding of the peptide in biphasic manner (Uversky et al, 2001 ). Mane and Stepanova ( 2016 ) investigated the folding dynamics of alpha-synuclein in initially unfolded form in water using an all-atom molecular dynamics simulations and essential dynamics (Mane and Stepanova, 2016 ). The synuclein constructs included a monomer, dimer and a tetramer.…”

Section: Discussionmentioning

confidence: 99%

“…The sodium and chloride ions were added to neutralize the positive charge of the peptide. The choice of using sodium chloride is based on the large number of previous molecular dynamics studies on alpha-synuclein where sodium chloride has been used (Herrera et al, 2008 ; Cino et al, 2012 ; Tian et al, 2012 ; Vekrellis and Stefanis, 2012 ; Vermaas and Tajkhorshid, 2014 ; Mane and Stepanova, 2016 ). Long range electrostatic interactions were computed using Particle Mesh Ewald method (Darden et al, 1993 ; Essmann et al, 1995 ) with a grid spacing of 0.12.…”

Section: Methodsmentioning

confidence: 99%

Conformational Ensembles of α-Synuclein Derived Peptide with Different Osmolytes from Temperature Replica Exchange Sampling

et al. 2017

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Intrinsically disordered proteins (IDP) are a class of proteins that do not have a stable three-dimensional structure and can adopt a range of conformations playing various vital functional role. Alpha-synuclein is one such IDP which can aggregate into toxic protofibrils and has been associated largely with Parkinson's disease (PD) along with other neurodegenerative diseases. Osmolytes are small organic compounds that can alter the environment around the proteins by acting as denaturants or protectants for the proteins. In the present study, we have conducted a series of replica exchange molecular dynamics simulations to explore the role of osmolytes, urea which is a denaturant and TMAO (trimethylamine N-oxide), a protecting osmolyte, in aggregation and conformations of the synuclein peptide. We observed that both the osmolytes have significantly distinct impacts on the peptide and led to transitions of the conformations of the peptide from one state to other. Our findings highlighted that urea attenuated peptide aggregation and resulted in the formation of extended peptide structures whereas TMAO led to compact and folded forms of the peptide.

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“…They found that TMAO induced the α-synuclein to fold back to compact conformation and suggested a biphasic mechanism of α-synuclein [135]. Another group used an all-atom molecular dynamic simulations and essential dynamics approach to study the dynamics of folding of unfolded α-synuclein present in water [136]. They used a monomer, dimer, and a tetramer of α-synuclein forms in their study.…”

Section: Effects Of Osmolytes On α-Synucleinmentioning

confidence: 99%

Role of Osmolytes in Amyloidosis

Khan¹,

Mueed²,

Deval³

et al. 2020

Synucleins - Biochemistry and Role in Diseases

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Osmolytes are naturally occurring small organic molecules present in all kingdoms of life. These organic molecules are accumulated by living systems to circumvent stress conditions. A number of human diseases have been grouped under the protein-misfolding diseases. These entire diseases share the same hallmarks of the presence of cellular inclusions and plaques that are deposited in the cells and tissues affected by the disease. These misfolded forms of protein are responsible for initiating toxic cascades in the cell, causing vesicle dystrafficking, synaptic and cell organelle dysfunction, and ultimately cell death. Published results suggest that cells regulate many biological processes such as protein folding, protein disaggregation, and protein-protein interactions via accumulation of specific osmolytes. Since, as of now, complete cure for these protein-misfolding disorders does not exist; therefore, it becomes increasingly important to review the recent works on this aspect to develop strategies for therapeutics. It has been shown that certain osmolytes can prevent the proteins from misfolding. Thus, osmolytes can be utilized as therapeutics for such diseases. In this review article, we discuss the role of naturally occurring osmolytes in various forms of amyloidosis associated with human diseases.

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Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

Cited by 17 publications

References 73 publications

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

Conformational Ensembles of α-Synuclein Derived Peptide with Different Osmolytes from Temperature Replica Exchange Sampling

Role of Osmolytes in Amyloidosis

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