Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins
Mingfu Liang,
Gaowei Jin,
Xingqiao Xie,
Wenchao Zhang,
Kaiyue Li,
Fengfeng Niu,
Cong Yu,
Zhiyi Wei
Affiliations
Mingfu Liang
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Gaowei Jin
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Xingqiao Xie
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Wenchao Zhang
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Kaiyue Li
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Fengfeng Niu
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
Cong Yu
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, Guangdong 518055, China; Corresponding author
Zhiyi Wei
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Brain Research Center, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Corresponding author
Summary: 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.
