Alteration of the α‐Synuclein Folding Landscape by a Mutation Related to Parkinson’s Disease

Ferreon, Allan Chris M.; Moran, Crystal R.; Ferreon, Josephine C.; Deniz, Ashok A.

doi:10.1002/ange.201000378

Cited by 19 publications

(33 citation statements)

References 37 publications

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“…19,36–40 CD and other NMR studies show minor differences in the preference for secondary structure between the mutants and the wildtype, but no difference represents a significant population within the broad ensemble that can explain the difference in aggregation behavior of the familial mutants with that of the wild type. 36,38,39 Molecular dynamics simulations have produced similarly conflicting reports. 37,40,41 Therefore, the key factor that drives these mutants to be so much more aggregation prone and pathogenic in nature than the WT and causes early onset of PD is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Effects of Mutations on the Reconfiguration Rate of α-Synuclein

et al. 2015

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It is still poorly understood why α-synuclein, the intrinsically disordered protein involved in Parkinson’s and other neurodegenerative diseases, is so prone to aggregation. Recent work has shown a correlation between the aggregation rate and the rate of diffusional reconfiguration by varying temperature and pH. Here we examine the effects of several point mutations in the sequence on the conformational ensemble and reconfiguration rate. We find that at lower temperatures the PD causing aggregation enhancing mutations slow down and aggregation reducing mutations drastically speed up intramolecular diffusion, as compared to the wild type sequence. However, at higher temperatures, one of three familial mutations that enhance aggregation slows intramolecular diffusion while non-natural mutations that inhibit aggregation speed up intramolecular diffusion. These results support the hypothesis that the first step of aggregation is kinetically controlled by reconfiguration in which the protein chain cannot reconfigure rapidly enough to escape oligomerization. Finally we provide physical and chemical insights into why small point mutations cause these dramatic changes in the conformational ensemble and dynamics.

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Section: Discussionmentioning

confidence: 99%

Effects of Mutations on the Reconfiguration Rate of α-Synuclein

et al. 2015

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“…The reported single-molecule results could be of relevance to the in vivo function of α-synuclein, the protein’s natural membrane interactions, and its propensity to misfold and aggregate. smFRET data in a subsequent paper [56] showed that the mutation A30P associated with early-onset Parkinson’s disease has a pronounced effect on the protein’s folding-binding landscape. Other smFRET studies have provided similar interesting information about some aspects of wild-type α-synuclein folding-binding properties [95, 96].…”

Section: Other Novel Insights Into Protein Biophysics and Biologymentioning

confidence: 99%

Protein folding at single-molecule resolution

Ferreon

Deniz

2011

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The protein folding reaction carries great significance for cellular function and hence continues to be the research focus of a large interdisciplinary protein science community. Single-molecule methods are providing new and powerful tools for dissecting the mechanisms of this complex process by virtue of their ability to provide views of protein structure and dynamics without associated ensemble averaging. This review briefly introduces common FRET and force methods, and then explores several areas of protein folding where single-molecule experiments have yielded insights. These include exciting new information about folding landscapes, dynamics, intermediates, unfolded ensembles, intrinsically disordered proteins, assisted folding and biomechanical unfolding. Emerging and future work is expected to include advances in singlemolecule techniques aimed at such investigations, and increasing work on more complex systems from both the physics and biology standpoints, including folding and dynamics of systems of interacting proteins and of proteins in cells and organisms.

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“…Upon interaction with the membrane surface, α-synuclein can adopt two major types of structures, namely, broken horseshoe-type helix [28], [36] and extended helix [36], [47]. Recent single molecule experiments have provided direct and compelling evidence in favor of the two switchable conformational states [48]–[51].…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Insights into the Membrane-Bound α-Synuclein

et al. 2013

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Membrane-induced disorder-to-helix transition of α-synuclein, a presynaptic protein, has been implicated in a number of important neuronal functions as well as in the etiology of Parkinson’s disease. In order to obtain structural insights of membrane-bound α-synuclein at the residue-specific resolution, we took advantage of the fact that the protein is devoid of tryptophan and incorporated single tryptophan at various residue positions along the sequence. These tryptophans were used as site-specific markers to characterize the structural and dynamical aspects of α-synuclein on the negatively charged small unilamellar lipid vesicles. An array of site-specific fluorescence readouts, such as the spectral-shift, quenching efficiency and anisotropy, allowed us to discern various features of the conformational rearrangements occurring at different locations of α-synuclein on the lipid membrane. In order to define the spatial localization of various regions of the protein near the membrane surface, we utilized a unique and sensitive indicator, namely, red-edge excitation shift (REES), which originates when a fluorophore is located in a highly ordered micro-environment. The extent of REES observed at different residue positions allowed us to directly identify the residues that are localized at the membrane-water interface comprising a thin (∼ 15 Å) layer of motionally restrained water molecules and enabled us to construct a dynamic hydration map of the protein. The combination of site-specific fluorescence readouts allowed us to unravel the intriguing molecular details of α-synuclein on the lipid membrane in a direct model-free fashion. Additionally, the combination of methodologies described here are capable of distinguishing subtle but important structural alterations of α-synuclein bound to different negatively charged lipids with varied head-group chemistry. We believe that the structural modulations of α-synuclein on the membrane could potentially be related to its physiological functions as well as to the onset of Parkinson’s diseases.

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Alteration of the α‐Synuclein Folding Landscape by a Mutation Related to Parkinson’s Disease

Cited by 19 publications

References 37 publications

Effects of Mutations on the Reconfiguration Rate of α-Synuclein

Effects of Mutations on the Reconfiguration Rate of α-Synuclein

Protein folding at single-molecule resolution

Structural and Dynamical Insights into the Membrane-Bound α-Synuclein

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