TY - JOUR
T1 - Functional synergy between the Munc13 C-terminal C1 and C2 domains
AU - Liu, Xiaoxia
AU - Seven, Alpay Burak
AU - Camacho, Marcial
AU - Esser, Victoria
AU - Xu, Junjie
AU - Trimbuch, Thorsten
AU - Quade, Bradley
AU - Su, Lijing
AU - Ma, Cong
AU - Rosenmund, Christian
AU - Rizo, Josep
N1 - Publisher Copyright:
© Liu et al.
PY - 2016/5/23
Y1 - 2016/5/23
N2 - Neurotransmitter release requires SNARE complexes to bring membranes together, NSF-SNAPs to recycle the SNAREs, Munc18-1 and Munc13s to orchestrate SNARE complex assembly, and Synaptotagmin-1 to trigger fast Ca2+-dependent membrane fusion. However, it is unclear whether Munc13s function upstream and/or downstream of SNARE complex assembly, and how the actions of their multiple domains are integrated. Reconstitution, liposome-clustering and electrophysiological experiments now reveal a functional synergy between the C1, C2B and C2C domains of Munc13-1, indicating that these domains help bridging the vesicle and plasma membranes to facilitate stimulation of SNARE complex assembly by the Munc13-1 MUN domain. Our reconstitution data also suggest that Munc18-1, Munc13-1, NSF, αSNAP and the SNAREs are critical to form a ‘primed’ state that does not fuse but is ready for fast fusion upon Ca2+ influx. Overall, our results support a model whereby the multiple domains of Munc13s cooperate to coordinate synaptic vesicle docking, priming and fusion.
AB - Neurotransmitter release requires SNARE complexes to bring membranes together, NSF-SNAPs to recycle the SNAREs, Munc18-1 and Munc13s to orchestrate SNARE complex assembly, and Synaptotagmin-1 to trigger fast Ca2+-dependent membrane fusion. However, it is unclear whether Munc13s function upstream and/or downstream of SNARE complex assembly, and how the actions of their multiple domains are integrated. Reconstitution, liposome-clustering and electrophysiological experiments now reveal a functional synergy between the C1, C2B and C2C domains of Munc13-1, indicating that these domains help bridging the vesicle and plasma membranes to facilitate stimulation of SNARE complex assembly by the Munc13-1 MUN domain. Our reconstitution data also suggest that Munc18-1, Munc13-1, NSF, αSNAP and the SNAREs are critical to form a ‘primed’ state that does not fuse but is ready for fast fusion upon Ca2+ influx. Overall, our results support a model whereby the multiple domains of Munc13s cooperate to coordinate synaptic vesicle docking, priming and fusion.
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U2 - 10.7554/eLife.13696
DO - 10.7554/eLife.13696
M3 - Article
C2 - 27213521
AN - SCOPUS:84979666746
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - MAY2016
M1 - e13696
ER -