COPII 囊泡生物发生起始的结构基础。
Structural basis for the initiation of COPII vesicle biogenesis.
机构信息
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14850, USA.
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14850, USA.
出版信息
Structure. 2021 Aug 5;29(8):859-872.e6. doi: 10.1016/j.str.2021.03.013. Epub 2021 Apr 7.
The first stage of the eukaryotic secretory pathway is the packaging of cargo proteins into coat protein complex II (COPII) vesicles exiting the ER. The cytoplasmic COPII vesicle coat machinery is recruited to the ER membrane by the activated, GTP-bound, form of the conserved Sar1 GTPase. Activation of Sar1 on the surface of the ER by Sec12, a membrane-anchored GEF (guanine nucleotide exchange factor), is therefore the initiating step of the secretory pathway. Here we report the structure of the complex between Sar1 and the cytoplasmic GEF domain of Sec12, both from Saccharomyces cerevisiae. This structure, representing a key nucleotide-free activation intermediate, reveals how the potassium ion-binding K loop disrupts the nucleotide-binding site of Sar1. We propose an unexpected orientation of the GEF domain relative to the membrane surface and postulate a mechanism for how Sec12 facilitates membrane insertion of the amphipathic helix exposed by Sar1 upon GTP binding.
真核生物分泌途径的第一阶段是将货物蛋白包装到离开内质网的衣壳蛋白复合物 II（COPII）小泡中。细胞质 COPII 小泡外壳机制通过激活的、结合 GTP 的保守 Sar1 GTP 酶的形式被募集到内质网膜上。Sec12，一种膜锚定的鸟苷酸交换因子（guanine nucleotide exchange factor），在 ER 表面上激活 Sar1，因此是分泌途径的起始步骤。在这里，我们报告了来自酿酒酵母的 Sar1 和细胞质 Sec12 的 GEF 结构域之间的复合物的结构。该结构代表了一个关键的无核苷酸激活中间物，揭示了钾离子结合 K 环如何破坏 Sar1 的核苷酸结合位点。我们提出了一个意想不到的 GEF 结构域相对于膜表面的取向，并假设了 Sec12 如何促进 Sar1 结合 GTP 时暴露的两亲螺旋的膜插入的机制。
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