Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Mol Cell. 2023 Jun 1;83(11):1856-1871.e9. doi: 10.1016/j.molcel.2023.05.009.
The pentameric FERRY Rab5 effector complex is a molecular link between mRNA and early endosomes in mRNA intracellular distribution. Here, we determine the cryo-EM structure of human FERRY. It reveals a unique clamp-like architecture that bears no resemblance to any known structure of Rab effectors. A combination of functional and mutational studies reveals that while the Fy-2 C-terminal coiled-coil acts as binding region for Fy-1/3 and Rab5, both coiled-coils and Fy-5 concur to bind mRNA. Mutations causing truncations of Fy-2 in patients with neurological disorders impair Rab5 binding or FERRY complex assembly. Thus, Fy-2 serves as a binding hub connecting all five complex subunits and mediating the binding to mRNA and early endosomes via Rab5. Our study provides mechanistic insights into long-distance mRNA transport and demonstrates that the particular architecture of FERRY is closely linked to a previously undescribed mode of RNA binding, involving coiled-coil domains.
五聚体 FERRY Rab5 效应物复合物是 mRNA 细胞内分布中 mRNA 与早期内体之间的分子连接。在这里，我们确定了人类 FERRY 的冷冻电镜结构。它揭示了一种独特的夹状结构，与任何已知的 Rab 效应物结构都没有相似之处。功能和突变研究的结合表明，虽然 Fy-2 C 端卷曲螺旋作为 Fy-1/3 和 Rab5 的结合区域，但两个卷曲螺旋和 Fy-5 都协同结合 mRNA。导致神经发育障碍患者 Fy-2 截断的突变会损害 Rab5 结合或 FERRY 复合物组装。因此，Fy-2 充当连接所有五个复合物亚基的结合枢纽，并通过 Rab5 介导与 mRNA 和早期内体的结合。我们的研究提供了对远距离 mRNA 运输的机制见解，并表明 FERRY 的特殊结构与以前未描述的 RNA 结合模式密切相关，涉及卷曲螺旋结构域。
