Multifunctions of α-Synuclein Explained by Its Dynamic Heterogeneous Conformations with a Hierarchy of Transition Times

Jiaxing Chen, Sofia Zaer, Paz Drori, Joanna Zamel, Khalil Joron, Nir Kalisman, Eitan Lerner, Nikolay V. Dokholyan

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α-Synuclein plays essential roles in synaptic vesicle homeostasis and neurotransmitter release through the interaction with membrane, while α-synuclein aggregates have been associated with several neurodegenerative diseases, especially Parkinson's disease. The different roles of α-synuclein could be attributed to the heterogenous conformations adopted by this intrinsically disordered protein. To demystify the physiological functions of α-synuclein and understand its pathogenic mechanism of Parkinson's disease, characterizing the monomeric structural ensemble and identifying the aggregation-prone and non-aggregation-prone structures are of particular importance. Here, we use inter-residue distance distributions derived from time-resolved FRET experiments as constraints to guide discrete molecular dynamics simulations of α-synuclein monomer. We explore the conformational space of α-synuclein and verify the generated conformational ensemble by additional experiments including far-UV circular dichroism spectrum and cross-linking mass spectrometry. We find that some conformational states of α-synuclein are surprisingly stable displaying dynamic transitions less than milliseconds. A comprehensive analysis of the conformational ensemble uncovers important structural features and potential conformations that are critical to stabilize the monomeric state or induce different oligomerization pathways.

Original languageEnglish
Title of host publicationThe FASEB Journal
Number of pages1
Volume36, S1
StatePublished - 1 May 2022

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