Department of Molecular Biology and Genetics/Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
Department of Molecular Biology and Genetics/Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
Dev Cell. 2019 Jan 7;48(1):100-114.e9. doi: 10.1016/j.devcel.2018.11.013. Epub 2018 Dec 6.
Correct localization of Rab GTPases in cells is critical for proper function in membrane trafficking, yet the mechanisms that target Rabs to specific subcellular compartments remain controversial. Guanine nucleotide exchange factors (GEFs) activate and consequently stabilize Rab substrates on membranes, thus implicating GEFs as the primary determinants of Rab localization. A competing hypothesis is that the Rab C-terminal hypervariable domain (HVD) serves as a subcellular targeting signal. In this study, we present a unifying mechanism in which the HVD controls targeting of certain Rabs by mediating interaction with their GEFs. We demonstrate that the TRAPP complexes, two related GEFs that use the same catalytic site to activate distinct Rabs, distinguish between Ypt1 (Rab1) and Ypt31/32 (Rab11) via their divergent HVDs. Remarkably, we find that HVD length gates Rab access to the TRAPPII complex by constraining the distance between the nucleotide-binding domain and the membrane surface.
正确定位 Rab GTPases 在细胞中对于膜运输的正常功能至关重要，但将 Rab 靶向特定亚细胞隔室的机制仍存在争议。鸟嘌呤核苷酸交换因子 (GEF) 可激活 Rab 底物并使其在膜上稳定，因此 GEF 被认为是 Rab 定位的主要决定因素。另一种竞争假说认为 Rab C 末端超变区 (HVD) 可作为亚细胞靶向信号。在本研究中，我们提出了一个统一的机制，其中 HVD 通过介导与 GEF 的相互作用来控制某些 Rab 的靶向。我们证明，TRAPP 复合物（两种相关的 GEF，它们使用相同的催化位点激活不同的 Rab）通过其不同的 HVD 区分 Ypt1（Rab1）和 Ypt31/32（Rab11）。值得注意的是，我们发现 HVD 的长度通过限制核苷酸结合域和膜表面之间的距离来控制 Rab 进入 TRAPPII 复合物的通道。
