Rebuilding essential active zone functions within a synapse.
Rebuilding essential active zone functions within a synapse.
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DOI：
10.1016/j.neuron.2022.01.026
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发表时间：
2022-05-04
期刊：
影响因子：
16.2
通讯作者：
Kaeser, Pascal S.
中科院分区：
文献类型：
--
作者：
Tan, Chao;Wang, Shan Shan H.;de Nola, Giovanni;Kaeser, Pascal S.
突触前活动区是控制神经递质分泌的分子机器。它们形成囊泡对接和引发的位点，并将囊泡与Ca 2+结合以触发释放。活动区机制的复杂性使得确定其释放机制变得具有挑战性。同时敲除活性区蛋白RIM和ELKS破坏活性区组装，废除囊泡对接，并损害释放。我们在这里重建对接，启动和Ca 2+分泌耦合在这些突变体中，而不恢复活性区网络。RIM锌指的再表达将Munc 13募集到未对接的囊泡，并使囊泡具有释放能力。通过将RIM锌指连接到CaVβ4-亚基，将这些引发的囊泡对接到Ca 2+通道，从而重建触发释放的动作电位。我们的工作确定了一个80 kDa的β4-Zn蛋白，它绕过了对兆道尔顿大小的分泌机器的需要，建立了融合能力和对接是机械分离的，并将RIM锌指-Munc 13复合物定义为活性区功能的枢纽。突触前活动区是巨道尔顿大小的蛋白质机器，用于神经递质释放的时空精度。Tan等人使用小蛋白质结构域消融活动区并重建其在突触内的功能。RIM锌指呈现未对接囊泡融合能力，和Ca 2+触发释放恢复拴这个启动域的Ca 2+通道。
Presynaptic active zones are molecular machines that control neurotransmitter secretion. They form sites for vesicle docking and priming, and couple vesicles to Ca2+ entry for release-triggering. The complexity of active zone machinery has made it challenging to determine its mechanisms in release. Simultaneous knockout of the active zone proteins RIM and ELKS disrupts active zone assembly, abolishes vesicle docking, and impairs release. We here rebuild docking, priming and Ca2+-secretion coupling in these mutants without reinstating active zone networks. Re-expression of RIM zinc fingers recruited Munc13 to undocked vesicles and rendered the vesicles release-competent. Action potential-triggering of release was reconstituted by docking these primed vesicles to Ca2+ channels through attaching RIM zinc fingers to CaVβ4-subunits. Our work identifies an 80-kDa β4-Zn protein that bypasses the need for megadalton-sized secretory machines, establishes that fusion competence and docking are mechanistically separable, and defines RIM zinc finger-Munc13 complexes as hubs for active zone function. Presynaptic active zones are megadalton-sized protein machines for spatiotemporal precision of neurotransmitter release. Tan et al. ablate active zones and rebuild their functions within synapses using small protein domains. RIM zinc fingers rendered undocked vesicles fusion-competent, and Ca2+-triggering of release was restored by tethering this priming domain to Ca2+ channels.
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影响因子：
16.2
作者：
de Jong APH;Roggero CM;Ho MR;Wong MY;Brautigam CA;Rizo J;Kaeser PS
通讯作者：
Kaeser PS
影响因子：
11.1
作者：
Al-Moyed, Hanan;Cepeda, Andreia P.;Reisinger, Ellen
通讯作者：
Reisinger, Ellen
影响因子：
16.6
作者：
Camacho M;Basu J;Trimbuch T;Chang S;Pulido-Lozano C;Chang SS;Duluvova I;Abo-Rady M;Rizo J;Rosenmund C
通讯作者：
Rosenmund C
影响因子：
16.6
作者：
Emperador-Melero J;Wong MY;Wang SSH;de Nola G;Nyitrai H;Kirchhausen T;Kaeser PS
通讯作者：
Kaeser PS
DOI：
10.1073/pnas.1605256113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Grauel, M. Katharina;Maglione, Marta;Rosenmund, Christian
通讯作者：
Rosenmund, Christian