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Wu, Xiandeng; Cai, Qixu; Shen, Zeyu; Chen, Xudong; Zeng, Menglong; Du, Shengwang; Zhang, Mingjie
Molecular cell, 03/2019, Volume: 73, Issue: 5Journal Article
Both the timing and kinetics of neurotransmitter release depend on the positioning of clustered Ca2+ channels in active zones to docked synaptic vesicles on presynaptic plasma membranes. However, how active zones form is not known. Here, we show that RIM and RIM-BP, via specific multivalent bindings, form dynamic and condensed assemblies through liquid-liquid phase separation. Voltage-gated Ca2+ channels (VGCCs), via C-terminal-tail-mediated direct binding to both RIM and RIM-BP, can be enriched to the RIM and RIM-BP condensates. We further show that RIM and RIM-BP, together with VGCCs, form dense clusters on the supported lipid membrane bilayers via phase separation. Therefore, RIMs and RIM-BPs are plausible organizers of active zones, and the formation of RIM and RIM-BP condensates may cluster VGCCs into nano- or microdomains and position the clustered Ca2+ channels with Ca2+ sensors on docked vesicles for efficient and precise synaptic transmissions. Display omitted •RIM and RIM-BP mixture forms liquid-liquid phase-separation-mediated condensates•Specific multivalent interaction between RIM and RIM-BP is essential for the LLPS•RIM and RIM-BP condensates cluster Ca2+ channels in solution and on membrane surface•RIM and RIM-BP are plausible organizers of presynaptic active zones Clustering of Ca2+ channels at presynaptic active zones is critical for precise control of neurotransmitter release. Wu et al. show that the presynaptic active zone scaffold proteins RIM and RIM-BP form self-assembled condensates via liquid-liquid phase separations capable of clustering voltage-gated Ca2+ channels on lipid membrane bilayers.
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