Structural basis of mRNA binding by the human FERRY Rab5 effector complex

• DOI: 10.1016/j.molcel.2023.05.009
• Publication Date: 2023-06-01T14:55:23Z
• Authors: Dennis Quentin; Jan S. Schuhmacher; Björn U. Klink; Jeni Lauer; Tanvir R. Shaikh; Pim J. Huis in ’t...; Luisa M. Welp; Henning Urlaub; Marino Zerial; Stefan Raunser
• Keywords: Vesicular Transport Proteins; Humans; Endosomes; rab5 GTP-Binding Proteins

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.