α-synuclein dimer structures found from computational simulations

Sahu, Kamlesh Kumar; Woodside, Michael T.; Tuszyński, Jack A.

doi:10.1016/j.biochi.2015.07.011

Cited by 16 publications

(13 citation statements)

References 62 publications

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“…We suggest further that closely packed AS molecules constituting the fuzzy layer of the fbs engage in local interactions, including the formation of intermolecular anti-parallel β-sheets or interacting helical regions (Sahu et al 2015 ) defining and stabilizing a form of dimer. In previous studies of the acceleration of fibrillation by polyamines (Fernandez et al 2004 ) and AS-coated quantum dots (Roberti et al 2009 ) we inferred that AS dimers coupled to the release of long-range interactions in the monomer (Bertoncini et al 2005 ) facilitate nucleation.…”

Section: Discussionmentioning

confidence: 74%

Pre-aggregation kinetics and intermediates of α-synuclein monitored by the ESIPT probe 7MFE

Fauerbach

Jovin

2017

Eur Biophys J

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The defining feature of the extensive family of amyloid diseases is the formation of networks of entangled elongated protein fibrils and amorphous aggregates exhibiting crossed β-sheet secondary structure. The time course of amyloid conversion has been studied extensively in vitro with the proteins involved in the neurodegenerative pathology of Parkinson’s disease (α-synuclein), Alzheimer’s disease (Tau) and Huntington’s disease (Huntingtin). Although much is known about the thermodynamics and kinetics of the transition from a soluble, intrinsically disordered monomer to the fibrillar end state, the putative oligomeric intermediates, currently considered to be the major initiators of cellular toxicity, are as yet poorly defined. We have detected and characterized amyloid precursors by monitoring AS aggregation with ESIPT (excited state intramolecular protein transfer) probes, one of which, 7MFE [7-(3-maleimido-N-propanamide)-2-(4-diethyaminophenyl)-3-hydroxychromone], is introduced here and compared with a related compound, 6MFC, used previously. A series of 140 spectra for sparsely labeled AS was acquired during the course of aggregation, and resolved into the relative contributions (spectra, intensities) of discrete molecular species including the monomeric, fibrillar, and ensemble of intermediate forms. Based on these findings, a kinetic scheme was devised to simulate progress curves as a function of key parameters. An essential feature of the model, one not previously invoked in schemes of amyloid aggregation, is the catalysis of molecular fuzziness by discrete colloidal nanoparticles arising spontaneously via monomer condensation upon exposure of AS to ≥ 37 °C.Electronic supplementary materialThe online version of this article (10.1007/s00249-017-1272-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 74%

Pre-aggregation kinetics and intermediates of α-synuclein monitored by the ESIPT probe 7MFE

Fauerbach

Jovin

2017

Eur Biophys J

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“…While some evidences support the existence of a stable cytosolic tetrameric form of the protein, other studies have shown that it can be found as a disordered monomer in the central nervous system (CNS) and other mammalian cells or that these forms both coexist in a dynamic equilibrium [50, 51]. More recently, the existence of a stable dimer has been suggested by computational evidences [52]. As for the aminoacidic sites involved in the interaction with membranes, numerous studies have reported a key role for the ones located at the N-terminal portion of α -synuclein [53].…”

Section: Alpha-synuclein Function At the Dopamine Synapsementioning

confidence: 99%

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

et al. 2017

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Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of α-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

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“…[25][26][27] Molecular docking and MD simulations on α-syn showed that β-sheet rich oligomers are less stable than α-helical oligomers. 28 Another study showed that β-sheet rich oligomers are more compact than helical oligomers suggesting that they could be the precursors of fibrils. 28 Furthermore, the aggregation pathways are highly dependent on the β-sheet propensity of the peptide, i.e., high β-sheet propensity leads to rapid aggregation into fibrillar structures, whereas low β-content leads to the formation of long-lived intermediate oligomers before fiber formation.…”

Section: Introductionmentioning

confidence: 99%

“…28 Another study showed that β-sheet rich oligomers are more compact than helical oligomers suggesting that they could be the precursors of fibrils. 28 Furthermore, the aggregation pathways are highly dependent on the β-sheet propensity of the peptide, i.e., high β-sheet propensity leads to rapid aggregation into fibrillar structures, whereas low β-content leads to the formation of long-lived intermediate oligomers before fiber formation. 29 The most intensively used coarse grained models for IDPs are lattice models, in which each residue is represented by a single particle occupying one site on a cubic lattice, while all unoccupied sites are considered as solvent.…”

Section: Introductionmentioning

confidence: 99%

The attachment of α-synuclein to a fiber: A coarse-grain approach

Ilie

Otter

Briels

2017

The Journal of Chemical Physics

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We present simulations of the amyloidogenic core of α-synuclein, the protein causing Parkinson's disease, as a short chain of coarse-grain patchy particles. Each particle represents a sequence of about a dozen amino acids. The fluctuating secondary structure of this intrinsically disordered protein is modelled by dynamic variations of the shape and interaction characteristics of the patchy particles, ranging from spherical with weak isotropic attractions for the disordered state to spherocylindrical with strong directional interactions for a β-sheet. Flexible linkers between the particles enable sampling of the tertiary structure. This novel model is applied here to study the growth of an amyloid fibril, by calculating the free energy profile of a protein attaching to the end of a fibril. The simulation results suggest that the attaching protein readily becomes trapped in a mis-folded state, thereby inhibiting further growth of the fibril until the protein has readjusted to conform to the fibril structure, in line with experimental findings and previous simulations on small fragments of other proteins.

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α-synuclein dimer structures found from computational simulations

Cited by 16 publications

References 62 publications

Pre-aggregation kinetics and intermediates of α-synuclein monitored by the ESIPT probe 7MFE

Pre-aggregation kinetics and intermediates of α-synuclein monitored by the ESIPT probe 7MFE

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

The attachment of α-synuclein to a fiber: A coarse-grain approach

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