TY - JOUR
T1 - RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of munc13
AU - Deng, Lunbin
AU - Kaeser, Pascal S.
AU - Xu, Wei
AU - Südhof, Thomas C.
N1 - Funding Information:
We thank H. Ly for technical assistance, Dr. Nils Brose for the gift of Munc13-antibodies and Munc13-2 KO mice, Dr. Z. Pang for the ubMunc13-2 ΔC2A construct, and members of the Südhof lab for comments. This work was supported by grants from the National Institites of Health (NINDS 33564 to T.C.S., DA029044 to P.S.K.), and by a Swiss National Science Foundation Postdoctoral Fellowship (to P.S.K.).
PY - 2011/1/27
Y1 - 2011/1/27
N2 - At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that-among others-mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn2+ finger domain of RIMs binds to the C2A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it. Here, we show that RIMs mediate vesicle priming not by coupling Munc13 to other active zone proteins as thought but by directly activating Munc13. Specifically, we found that the isolated Zn2+ finger domain of RIMs autonomously promoted vesicle priming by binding to Munc13, thereby relieving Munc13 homodimerization. Strikingly, constitutively monomeric mutants of Munc13 rescued priming in RIM-deficient synapses, whereas wild-type Munc13 did not. Both mutant and wild-type Munc13, however, rescued priming in Munc13-deficient synapses. Thus, homodimerization of Munc13 inhibits its priming function, and RIMs activate priming by disrupting Munc13 homodimerization.
AB - At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that-among others-mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn2+ finger domain of RIMs binds to the C2A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it. Here, we show that RIMs mediate vesicle priming not by coupling Munc13 to other active zone proteins as thought but by directly activating Munc13. Specifically, we found that the isolated Zn2+ finger domain of RIMs autonomously promoted vesicle priming by binding to Munc13, thereby relieving Munc13 homodimerization. Strikingly, constitutively monomeric mutants of Munc13 rescued priming in RIM-deficient synapses, whereas wild-type Munc13 did not. Both mutant and wild-type Munc13, however, rescued priming in Munc13-deficient synapses. Thus, homodimerization of Munc13 inhibits its priming function, and RIMs activate priming by disrupting Munc13 homodimerization.
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U2 - 10.1016/j.neuron.2011.01.005
DO - 10.1016/j.neuron.2011.01.005
M3 - Article
C2 - 21262469
AN - SCOPUS:78651504517
SN - 0896-6273
VL - 69
SP - 317
EP - 331
JO - Neuron
JF - Neuron
IS - 2
ER -