Synaptic scaffold proteins (e.g., liprin-α, ELKS, RIM, and RIM-BP) orchestrate ion channels, receptors, and enzymes at presynaptic terminals to form active zones for neurotransmitter release. The underlying mechanism of the active zone assembly remains elusive. Here, we report that liprin-α proteins have the potential to oligomerize through the N-terminal coiled-coil region. Our structural and biochemical characterizations reveal that a gain-of-function mutation promotes the self-assembly of the coiled coils in liprin-α2 by disrupting intramolecular interactions and promoting intermolecular interactions. By enabling multivalent interactions with ELKS proteins, the oligomerized coiled-coil region of liprin-α2 enhances the phase separation of the ELKS N-terminal segment. We further show that liprin-α2, by regulating the interplay between two phase separations of ELKS and RIM/RIM-BP, controls the protein distributions. These results imply that the complicated protein-protein interactions allow liprin-α to function with the active zone scaffolds and compartmentalize protein assemblies to achieve comprehensive functions in the active zone.
Keywords: CAST; ERC1; ERC2; LLPS; SYD-2; presynaptic active zone; protein condensate; protein-protein interaction.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.