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

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. [Display omitted] •FERRY links mRNA to early endosomes in long-range transport of transcripts•Unique clamp-like architecture of the pentameric FERRY Rab5 effector complex•Complex RNA binding interface mainly involves flexible coiled-coil domains of Fy-2•Neurological disorder-related mutations impair Rab5 binding and FERRY assembly The cryo-EM structure of the pentameric FERRY Rab5 effector complex in Quentin, Schuhmacher et al. sheds light on the elusive link between mRNA and early endosomes in long-range transport of transcripts. Its unique clamp-like architecture is closely linked to a novel mode of RNA binding, involving its terminal coiled-coil domains.