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

Poster Board Number: A89

Jiaxing Chen (Penn State College of Medicine), Sofia Zaer (The Hebrew University of Jerusalem), Paz Drori (The Hebrew University of Jerusalem), Joanna Zamel (The Hebrew University of Jerusalem), Khalil Joron (The Hebrew University of Jerusalem), Nir Kalisman (The Hebrew University of Jerusalem), Eitan Lerner (The Hebrew University of Jerusalem), Nikolay Dokholyan (Penn State College of Medicine)

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.

This work is supported by the National Institutes of Health (1R35 GM134864 and R01 GM130942), the Passan Foundation, the National Center for Advancing Translational Sciences (UL1 TR002014), the Israel Science Foundation (1768/15 and 3565/20), the Milner Fund, and the Hebrew University of Jerusalem (start-up funds).