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

Dennis Quentin, Jan S Schuhmacher, Björn U Klink, Jeni Lauer, Tanvir R Shaikh, Pim J Huis In 't Veld, Luisa M Welp, Henning Urlaub, Marino Zerial, Stefan Raunser

Molecular cell 2023 Jun 01

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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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Dennis Quentin, Jan S Schuhmacher, Björn U Klink, Jeni Lauer, Tanvir R Shaikh, Pim J Huis In 't Veld, Luisa M Welp, Henning Urlaub, Marino Zerial, Stefan Raunser. Structural basis of mRNA binding by the human FERRY Rab5 effector complex. Molecular cell. 2023 Jun 01;83(11):1856-1871.e9