Intrinsic Disorder in α-Synuclein Regulates the Exocytotic Fusion Pore Transition

Today, it is widely accepted that intrinsic disorder is strongly related to the cell cycle, during mitosis, differentiation, and apoptosis. Of particular interest are hybrid proteins possessing both structured and unstructured domains that are critical in human health and disease, such as a-synuclein. In this work, we describe how a-synuclein interacts with the nascent fusion pore as it evolves toward expansion. We unveil the key role played by its intrinsically disordered region as a thermodynamic regulator of the nucleation-expansion energy barrier. By analyzing a truncated variant of a-synuclein that lacks the disordered region, we find that the landscape of protein interactions with PIP2 and POPS lipids is highly altered, ultimately increasing the energy cost for the fusion pore to transit from nucleation to expansion. We conclude that the intrinsically disordered region in full-length a-synuclein recognizes and allocates pivotal protein:lipid interactions during membrane remodeling in the first stages of the fusion pore.

Automated summary

It is now widely accepted that intrinsic disorder is closely related to the cell cycle, particularly in hybrid proteins with both structured and unstructured domains. This study focuses on how a-synuclein interacts with the nascent fusion pore during its expansion process. The intrinsically disordered region of a-synuclein is found to play a crucial role as a thermodynamic regulator of the nucleation-expansion energy barrier. In addition, the absence of this disordered region alters the protein interactions with PIP2 and POPS lipids, increasing the energy cost for the fusion pore to transition from nucleation to expansion.