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

Chen, Jiaxing; Zaer, Sofia; Drori, Paz; Zamel, Joanna; Joron, Khalil; Kalisman, Nir; Lerner, Eitan; Dokholyan, Nikolay V.

doi:10.1016/j.str.2021.05.002

Cited by 44 publications

(82 citation statements)

References 135 publications

(205 reference statements)

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“…The conformational ensemble of α-Syn monomer indeed consists of structures that are similar to the membrane-bound state of α-Syn [170]. These contain partially folded helices involving N-terminuses and NAC domains similar to the 1XQ8 model [170], suggesting that such a type of folding might also be present in the early stages of aggregation. The C-terminal domain (residues 95-140) is flexible and predominantly consists of negatively charged amino acids [165].…”

Section: Misfolding and Aggregation Of α-Synmentioning

confidence: 85%

“…NAC is also part of the membrane-binding domain of the protein [167]. The conformational ensemble of α-Syn monomer indeed consists of structures that are similar to the membrane-bound state of α-Syn [170]. These contain partially folded helices involving N-terminuses and NAC domains similar to the 1XQ8 model [170], suggesting that such a type of folding might also be present in the early stages of aggregation.…”

Section: Misfolding and Aggregation Of α-Synmentioning

confidence: 94%

“…Moreover, multiple species coexist at different stages of the aggregation kinetics [17,303,304], suggesting the involvement of aggregation intermediates in dictating the polymorphism. The mapping of the conformational space of α-Syn monomer reveals a structural subpopulation of α-Syn monomer that promotes its binding with membranes and induces the formation of various oligomers and fibrils [170]. Our lab recently demonstrated that the heterogeneous nucleation during the aggregation pathway forms the basis of the origin of polymorphism [252].…”

Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 98%

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Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Mehra¹,

Gadhe²,

Bera³

et al. 2021

Biomolecules

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Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson’s disease dementia (PDD), and even subsets of Alzheimer’s disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure–pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.

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Section: Misfolding and Aggregation Of α-Synmentioning

confidence: 85%

Section: Misfolding and Aggregation Of α-Synmentioning

confidence: 94%

Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 98%

See 1 more Smart Citation

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Mehra¹,

Gadhe²,

Bera³

et al. 2021

Biomolecules

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“… 19 DMD simulations can also incorporate experimentally derived structural and dynamic information as constraints to reconstruct experimentally consistent conformational ensembles for both structured proteins and IDPs. 20 , 21 We use SNAP-25 (synaptosomal-associated protein of 25 kDa) as a prototypical IDP for our system of study. SNAP-25, together with the synaptic vesicle protein Synaptobrevin 2 (or VAMP 2) and plasma membrane protein Syntaxin 1a, bind together to form a coiled 4-helix bundle as part of the SNARE (soluble N -ethylmaleimide-sensitive factor attachment receptor) complex.…”

Section: Introductionmentioning

confidence: 99%

Integrative structural dynamics probing of the conformational heterogeneity in synaptosomal-associated protein 25

Saikia

Yanez-Orozco

Qiu

et al. 2021

Cell Reports Physical Science

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SUMMARY SNAP-25 (synaptosomal-associated protein of 25 kDa) is a prototypical intrinsically disordered protein (IDP) that is unstructured by itself but forms coiled-coil helices in the SNARE complex. With high conformational heterogeneity, detailed structural dynamics of unbound SNAP-25 remain elusive. Here, we report an integrative method to probe the structural dynamics of SNAP-25 by combining replica-exchange discrete molecular dynamics (rxDMD) simulations and label-based experiments at ensemble and single-molecule levels. The rxDMD simulations systematically characterize the coil-to-molten globular transition and reconstruct structural ensemble consistent with prior ensemble experiments. Label-based experiments using Förster resonance energy transfer and double electron-electron resonance further probe the conformational dynamics of SNAP-25. Agreements between simulations and experiments under both ensemble and single-molecule conditions allow us to assign specific helix-coil transitions in SNAP-25 that occur in submillisecond timescales and potentially play a vital role in forming the SNARE complex. We expect that this integrative approach may help further our understanding of IDPs.

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“…These are often referred to as strains [44,73,80,81], a term borrowed from virology to indicate different structures produced by the same protein specimen. A growing body of evidence is indicating oligomers as the major toxic species during the amyloidogenesis that leads to neurodegeneration [82][83][84][85][86][87][88]. Indeed, the potential to effectively "seed" the aggregation, referring to the ability to contact and convert monomers and hence self-propagate, seems to be an emergent property of oligomers, defined as "prion-like behaviour" (detailed in the next section).…”

Section: The Paths Towards Toxicitymentioning

confidence: 99%

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Candelise

Scaricamazza

Salvatori

et al. 2021

IJMS

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Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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

Cited by 44 publications

References 135 publications

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Integrative structural dynamics probing of the conformational heterogeneity in synaptosomal-associated protein 25

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

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