RT Journal Article
SR Electronic
T1 The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.09.374991
DO 10.1101/2020.11.09.374991
A1 Jiaxing Chen
A1 Sofia Zaer
A1 Paz Drori
A1 Joanna Zamel
A1 Khalil Joron
A1 Nir Kalisman
A1 Eitan Lerner
A1 Nikolay V. Dokholyan
YR 2020
UL http://biorxiv.org/content/early/2020/11/09/2020.11.09.374991.abstract
AB The intrinsically disordered protein, α-synuclein, implicated in synaptic vesicle homeostasis and neurotransmitter release, is also associated with several neurodegenerative diseases. The different roles of α-synuclein are characterized by distinct structural states (membrane-bound, dimer, tetramer, oligomer, and fibril), which are originated from its various monomeric conformations. The pathological states, determined by the ensemble of α-synuclein monomer conformations and dynamic pathways of interconversion between dominant states, remain elusive due to their transient nature. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.Competing Interest StatementThe authors have declared no competing interest.