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N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine

Wang, C.; Zhao, C.; Xiao, H.; Qiang, J.; Liu, Z.; Gu, J.; Zhang, S.; Li, D.; Zhang, Y.; Burre, J.; Diao, J.; Liu, C.

2024-03-08 biophysics
10.1101/2024.03.04.583437 bioRxiv
Show abstract

Post-translational modifications (PTMs) of -synuclein (-syn) such as acetylation and phosphorylation play important yet distinct roles in regulating -syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate -syn function in presynaptic terminals remains unclear. Previously, we reported that -syn clusters synaptic vesicles (SV)1, and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering2. Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of -syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of -syns N-terminus and increased intermolecular interactions on the LPC-containing membrane. Our work demonstrates that N-acetylation fine-tunes -syn-LPC interaction for mediating -syns function in SV clustering.

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