Evidence for a Partially Folded Intermediate in α-Synuclein Fibril Formation*

By Vladimir N Uversky, Jie Li, A. Fink. Journal of Biological Chemistry, 2001

1,060 citations recorded by the source corpus.

Intracellular proteinaceous aggregates (Lewy bodies and Lewy neurites) of α-synuclein are hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple systemic atrophy. However, the molecular mechanisms underlying α-synuclein aggregation into such filamentous inclusions remain unknown. An intriguing aspect of this problem is that α-synuclein is a natively unfolded protein, with little or no ordered structure under physiological conditions. This raises the question of how an essentially disordered protein is transformed into highly organized fibrils. In the search for an answer to this question, we have investigated the effects of pH and temperature on the structural properties and fibrillation kinetics of human recombinant α-synuclein. Either a decrease in pH or an increase in temperature transformed α-synuclein into a partially folded conformation. The presence of this intermediate is strongly correlated with the enhanced formation of α-synuclein fibrils. We propose a model for the fibrillation of α-synuclein in which the first step is the conformational transformation of the natively unfolded protein into the aggregation-competent partially folded intermediate.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/551599d506582221f0ebbe3042c44153cb68e209

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Citations in the corpus

Α-synuclein misfolding and Parkinson's disease. (2012, background): “Incubation of α-synuclein with Al3+ leads to the changes in the far-UV CD, UV absorbance, intrinsic fluorescence and ANS fluorescence spectra consistent with the formation of the partially folded intermediates described above [247, 252].”
Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics (2019, background): “In fact, extended IDPs, such as α-synuclein [75], caldesmon 636-771 fragment [76], phosphodiesterase γ-subunit [77], the receptor extracellular domain of nerve growth factor [78], αs-casein [79], and several other IDPs are known to gain more ordered structure based on temperature, and are usually mo”
Assessing protein disorder and induced folding (2005, background): “It has been shown that IDPs with extended disorder are characterized by low (coil-like) intramolecular packing density, reflected by the absence of a maximum on their Kratky plots.(20,86,90,94,143) However, it is noteworthy that Kratky plots of premolten globules can give rise to a small bump follow”
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, methodology): “The nucleated polymerization model has been used to describe the aggregation of a range of systems including PrP (142), Aβ40 and Aβ42 (136), αs (143), polyGln sequences (144), insulin (145), and others.”
Natively unfolded proteins: A point where biology waits for physics (2002, background): “Self-association of an intrinsically unfolded -subunit of phosphodiesterase induced folding of this protein into a molten globule-like conformation (Uversky et al. 2002).”
Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen (2003, background): “The misfolded proteins then aggregate with each other and possibly also with additional proteins (Kopito, 2000; Trojanowski and Lee, 2000; Uversky et al., 2001; Walker and LeVine, 2001).”
The s2D method: simultaneous sequence-based prediction of the statistical populations of ordered and disordered regions in proteins. (2015, result): “This prediction is consistent with experimental measurements on the monomeric state of α-synuclein in solution, by both circular dichroism (CD) [50] and NMR spectroscopy [51], performed also in vivo in Escherichia coli cells [52].”
A decade and a half of protein intrinsic disorder: Biology still waits for physics (2013, background): “1, 73, [95] [96] [97] [98] These heating-induced structural changes in extended IDPs were attributed to the increased strength of the hydrophobic interaction at higher temperatures, leading to a stronger hydrophobic attraction, which is the major driving force for folding.”
Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death (2011, neutral): “Formation of pathological inclusions occurs by a multi-step process including the misfolding of normal soluble proteins, their association into higher order oligomers, followed by their assembly into amyloid fibrils that form disease specific inclusions (Conway et al., 2000; Uversky et al., 2001).”