Munc13 structural transitions and oligomers that may choreograph successive stages in vesicle priming for neurotransmitter release.
Munc13 structural transitions and oligomers that may choreograph successive stages in vesicle priming for neurotransmitter release.
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DOI：
10.1073/pnas.2121259119
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发表时间：
2022-02-15
影响因子：
11.1
通讯作者：
Rothman JE
中科院分区：
文献类型：
--
作者：
Grushin K;Kalyana Sundaram RV;Sindelar CV;Rothman JE
人类中枢神经系统中神经信息处理的速度最终取决于突触中化学物质传递的速度，因为动作电位的传递距离相对较短。因此，与其他形式的膜融合相比，含有神经递质的突触囊泡的释放必须非常快。六个独立的SNARE复合体合作实现这一目标。但每个囊泡下是如何精确地组装六个副本的呢？在这里，我们报告了组装SNAREs的关键分子伴侣的六个拷贝可以将自己排列成一个封闭的六边形，提供了可能的答案。六个SNARE复合体是如何在每个突触囊泡下组装的？在这里，我们报道了启动SNAREpin组装的关键伴侣Munc13的核心区域的低温电镜晶体结构。Munc13的功能核心由c1 - c2b - munc - c2c （Munc13C）组成，在两种不同构象的富含磷脂酰丝氨酸的双层之间自发结晶，每一种构象都处于完全不同的低聚态。在开放构象（状态1）中，Munc13C形成直立三聚体连接两个双层，将它们分开约21 nm。在封闭构象中，Munc13C的6个拷贝相互作用形成一个横向六聚体，高出双分子层约14 nm。开放构象和封闭构象的区别仅在于围绕柔性铰链的刚体旋转，当这种旋转进行时，Munc13协同组装成一个侧向六聚体（状态2），其中Munc13的关键SNARE组装激活位点被其邻居自动抑制。我们提出横向六聚体中的每个Munc13最终组装单个SNAREpin，解释了如何仅且准确地模板化六个SNARE复合物。我们认为状态1和状态2可能代表突触囊泡供应链中的两个连续状态，导致“启动”的准备释放囊泡，其中SNAREpins被夹住并准备释放（状态3）。
The speed of neural information processing in the human central nervous system is ultimately determined by the speed of chemical transmission at synapses, because action potentials have relatively short distances to traverse. The release of synaptic vesicles containing neurotransmitters must therefore be remarkably fast as compared to other forms of membrane fusion. Six separate SNARE complexes cooperate to achieve this. But how can exactly six copies be assembled under every vesicle? Here we report that six copies of the key molecular chaperone that assembles the SNAREs can arrange themselves into a closed hexagon, providing the likely answer. How can exactly six SNARE complexes be assembled under each synaptic vesicle? Here we report cryo-EM crystal structures of the core domain of Munc13, the key chaperone that initiates SNAREpin assembly. The functional core of Munc13, consisting of C1–C2B–MUN–C2C (Munc13C) spontaneously crystallizes between phosphatidylserine-rich bilayers in two distinct conformations, each in a radically different oligomeric state. In the open conformation (state 1), Munc13C forms upright trimers that link the two bilayers, separating them by ∼21 nm. In the closed conformation, six copies of Munc13C interact to form a lateral hexamer elevated ∼14 nm above the bilayer. Open and closed conformations differ only by a rigid body rotation around a flexible hinge, which when performed cooperatively assembles Munc13 into a lateral hexamer (state 2) in which the key SNARE assembly-activating site of Munc13 is autoinhibited by its neighbor. We propose that each Munc13 in the lateral hexamer ultimately assembles a single SNAREpin, explaining how only and exactly six SNARE complexes are templated. We suggest that state 1 and state 2 may represent two successive states in the synaptic vesicle supply chain leading to “primed” ready-release vesicles in which SNAREpins are clamped and ready to release (state 3).
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影响因子：
64.5
作者：
GEPPERT, M;GODA, Y;SUDHOF, TC
通讯作者：
SUDHOF, TC
影响因子：
56.9
作者：
BROSE, N;PETRENKO, AG;JAHN, R
通讯作者：
JAHN, R
DOI：
10.1073/pnas.0611318104
发表时间：
2007-02-20
影响因子：
11.1
作者：
Dulubova, Irina;Khvotchev, Mikhail;Rizo, Josep
通讯作者：
Rizo, Josep
Munc13-1 C（1）C（2）B区域的两个不同的膜结合面对神经递质的控制释放。
影响因子：
7.7
作者：
Camacho M;Quade B;Trimbuch T;Xu J;Sari L;Rizo J;Rosenmund C
通讯作者：
Rosenmund C
影响因子：
3.7
作者：
Prashad RC;Charlton MP
通讯作者：
Charlton MP