FERRY Rab5 Effector Complex
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Abstract
The FERRY complex is a pentameric early endosomal Rab5 effector that binds mRNA and links it to motile early endosomes for long-range intracellular transport, especially in neurons. The complex is composed of Fy-1, Fy-2, Fy-3, Fy-4 and Fy-5, with Fy-2 acting as the central organizing subunit.
Cryo-EM structures reveal a clamp-like architecture, a long six-helix bundle and extended coiled-coils that together create a unique RNA-binding surface.
Overall Structure of FERRY
FERRY assembles as a flexible clamp built around a Fy-4 dimer. Each arm of the clamp is formed by the six-helix bundle of Fy-2 associated with Fy-5. Long coiled-coils extending from Fy-2 stabilize accessory subunits and provide major RNA-binding regions.
Subunit Functions
- Fy-2 (Ppp1r21)
- Central structural hub of the complex
- Forms a hollow six-helix bundle that connects the two arms
- N- and C-terminal coiled-coils bind RNA and Rab5
- Provides binding sites for Fy-1, Fy-3, Fy-4 and Fy-5
- Fy-4 (Cryzl1)
- Rossmann-fold protein that forms a symmetric dimer
- Creates the rigid central body around which Fy-2 wraps
- Fy-5 (Gatd1)
- Small Rossmann-fold protein at the periphery of each arm
- Rotates relative to Fy-2 upon binding, increasing the contact surface
- Contributes a minor RNA-binding loop
- Fy-1 (Tbck) and Fy-3 (C12orf4)
- Accessory subunits that bind the C-terminal coiled-coil of Fy-2
- Not resolved in the core cryo-EM density, suggesting flexible positioning
RNA Binding Mechanism
The FERRY complex uses an unusual coiled-coil-based RNA-binding mechanism rather than classical RNA-binding domains.
Major RNA-binding regions:
- N-terminal coiled-coil of Fy-2
- C-terminal coiled-coil of Fy-2
- A loop region in Fy-5 (minor contribution)
Crosslinking experiments show that RNA contacts are distributed along the length of Fy-2 coiled-coils. Electrophoretic mobility shift assays indicate that the Fy-2/Fy-4/Fy-5 core can bind RNA efficiently, whereas Fy-2 alone cannot, showing that Fy-4 and Fy-5 are required to stabilize the correct conformation.
Mass photometry suggests that one mRNA molecule binds per FERRY complex, probably spanning the extended coiled-coil surface.
Rab5 Interaction
Rab5-GTP binds to a region in the C-terminal coiled-coil of Fy-2. Because Rab5 is anchored to early endosomal membranes via lipid modifications, this interaction recruits FERRY to early endosomes.
- Binding is specific for the active, GTP-loaded form of Rab5
- One or two Rab5 molecules may bind, consistent with the dimeric coiled-coil
- The complex is positioned approximately perpendicular to the membrane surface, allowing RNA to project into the cytoplasm while remaining attached to the moving organelle
Disease-Linked Mutations
- Fy-2 truncation (Arg697*)
A mutation that removes the last 84 residues of Fy-2:
- abolishes binding of Fy-1 and Fy-3
- removes the Rab5-binding region on the C-terminal coiled-coil
- leaves only a reduced 3-subunit core (Fy-2/Fy-4/Fy-5)
- is associated with severe neurodevelopmental defects
- Fy-5 P166S
- Point mutation located at the Fy-2 interaction surface
- Does not disrupt complex assembly or RNA binding in vitro
- May affect regulation or stability of the complex in cells
References
- Quentin**, D., Schuhmacher**, J. S., Klink, B. U., Lauer, J., Shaikh, T. R., Huis in ’t Veld, P. J., Welp, L. M., Urlaub, H., Zerial, M., Raunser, S. (2023). Structural basis of mRNA binding by the human FERRY Rab5 effector complex. Molecular Cell 83, 1856–1871. https://doi.org/10.1016/j.molcel.2023.05.009
About This Page
This page was created by Udit Pathak,(BI3323-Aug2025) Indian Institute of Science Education and Research (IISER) Pune.
