Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

McClendon, Sebastian; Rospigliosi, Carla C.; Eliezer, David

doi:10.1002/pro.149

Cited by 87 publications

(110 citation statements)

References 56 publications

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“…Instead, intermolecular electrostatic repulsion of the negatively charged C-terminus, hydrophobicity, and overall structural compactness may play a more prominent role in oligomerization [54][55][56][57]. For example, using single-molecule (sm) fluorescence resonance energy transfer (FRET), it was demonstrated that at low pH, charge neutralization at the C-terminus increases intramolecular contacts and allows inclusion into a hydrophobic cluster that is more aggregation prone [56].…”

Section: Intramolecular Interactions As Determinants Of Aggregationmentioning

confidence: 99%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

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Section: Intramolecular Interactions As Determinants Of Aggregationmentioning

confidence: 99%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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“…However, subsequent studies indicated that the E46K mutation increases such contacts, and that they are unaffected by the A30P and A53T mutations. Other conditions that increase the compactness of regions of the protein also lead to enhanced aggregation (34) whereas variants or conditions that reduce long-range interactions are associated with reduced aggregation (35, 36), Thus, it seems that long-range contacts may not be protective against aS aggregation and might even facilitate the process (37). …”

Section: Introductionmentioning

confidence: 99%

Folding and misfolding of alpha-synuclein on membranes

Dikiy

Eliezer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

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177

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The protein alpha-synuclein is considered to play a major role in the etiology of Parkinson’s disease. Because it is found in a classic amyloid fibril form within the characteristic intra-neuronal Lewy body deposits of the disease, aggregation of the protein is thought to be of critical importance, but the context in which the protein undergoes aggregation within cells remains unknown. The normal function of synucleins is poorly understood, but appears to involve membrane interactions, and in particular reversible binding to synaptic vesicle membranes. Structural studies of different states of alpha-synuclein, in the absence and presence of membranes or membrane mimetics, have led to models of how membrane-bound forms of the protein may contribute both to functional properties of the protein, as well as to membrane-induced self-assembly and aggregation. This article reviews this area, with a focus on a particular model that has emerged in the past few years.

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“…In vitro, the aggregation propensity of α-synuclein is very sensitive to solution conditions such as temperature, pH, salt concentration, and solution cofactors. There has been significant work to discover the structures that form in association with lipids, structures of final aggregates, and structures that may be the aggregation precursor (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). However, the underlying reason for why monomeric α-synuclein is so prone to aggregation is still unknown.…”

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confidence: 99%

Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion

Ahmad

Chen

Lapidus

2012

Proc. Natl. Acad. Sci. U.S.A.

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We hypothesize that the first step of aggregation of disordered proteins, such as α-synuclein, is controlled by the rate of backbone reconfiguration. When reconfiguration is fast, bimolecular association is not stable, but as reconfiguration slows, association is more stable and subsequent aggregation is faster. To investigate this hypothesis, we have measured the rate of intramolecular diffusion in α-synuclein, a protein involved in Parkinson's disease, under solvent conditions that accelerate or decelerate aggregation. Using the method of tryptophan-cysteine (Trp-Cys) quenching, the rate of intramolecular contact is measured in four different loops along the chain length. This intrinsically disordered protein is highly diffusive at low temperature at neutral pH, when aggregation is slow, and compacts and diffuses more slowly at high temperature or low pH, when aggregation is rapid. Diffusion also slows with the disease mutation A30P. This work provides unique insights into the earliest steps of α-synuclein aggregation pathway and should provide the basis for the development of drugs that can prevent aggregation at the initial stage.unfolded state | Alzheimer's disease | amyloid T he protein α-synuclein is the primary component of intracellular aggregants known as Lewy bodies, a hallmark of Parkinson's disease, and likely plays a central role in neuronal cell death (1). When recombinantly expressed and purified it is intrinsically disordered in solution and highly prone to aggregation (2). Recent work has shown that the native structure in human cells is likely a helical tetramer that is resistant to aggregation, but when this tetramer is denatured the monomers cannot autonomously refold and aggregate very quickly (3, 4). Thus it is likely that the aggregation pathway passes through the monomer. In vitro, the aggregation propensity of α-synuclein is very sensitive to solution conditions such as temperature, pH, salt concentration, and solution cofactors. There has been significant work to discover the structures that form in association with lipids, structures of final aggregates, and structures that may be the aggregation precursor (5-15). However, the underlying reason for why monomeric α-synuclein is so prone to aggregation is still unknown. We propose that a physical influence on aggregation is the internal dynamics of the disordered chain, that is, the rate of intramolecular diffusion.Over the past decade, a number of groups have measured intramolecular diffusion in a variety of sequences using measurements of intramolecular contact between two probes placed in the chain. All unstructured peptides, including fragments of α-synuclein, diffuse relatively rapidly, approximately 1-3 × 10 −6 cm 2 s −1 (16-18). These rates are less than 10 times slower than free diffusion of individual amino acids and about the same as translational diffusion of the entire chain, suggesting that the chain does not exert significant drag on the movement of individual segments (19), although there are measurable tail effects when ...

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Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

Cited by 87 publications

References 56 publications

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Folding and misfolding of alpha-synuclein on membranes

Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion

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