Structure of the human FERRY Rab5 effector complex

Abstract

Long-range mRNA transport is crucial for the spatio-temporal regulation of gene expression, and its malfunction is linked to neurological disorders. The pentameric FERRY Rab5 effector complex is the molecular link between mRNA and the early endosome in mRNA intracellular distribution. Here, we determine the cryo-EM structure of the human FERRY complex, composed of Fy-1 to Fy-5. The structure reveals a clamp-like architecture, in which two arm-like appendages, each consisting of Fy-2 and a Fy-5 dimer, protrude from the central Fy-4 dimer. We demonstrate that the coiled-coil domains of Fy-2 are flexible and project into opposite directions from the FERRY complex core. While the C-terminal coiled-coil acts as binding region for Fy-1/3 and Rab5, both coiled-coils together with Fy-5 bind mRNA. Thus, Fy-2 serves as binding hub that connects not only all five complex subunits, but also mediates the binding to mRNA and to the early endosome via Rab5. The FERRY structure provides novel mechanistic insight into long-distance mRNA transport.

A MademoiseLLE domain binding platform links the key RNA transporter to endosomes

“…In plants, two RRM-type RNA-binding proteins form a complex with cargo mRNAs and the endosomal component N -ethylmaleimide-sensitive factor NSF as well as Rab5a (Tian et al ., 2018; Tian et al ., 2020a; Tian et al ., 2020b). Comparably, the FERRY complex ( F ive-subunit E ndosomal R ab5 and R NA/ribosome intermediar Y ) interacts with the activated GTP-bound form of Rab5 during endosomal mRNA transport in neurons (Schuhmacher et al ., 2021; Quentin et al ., 2021). Further examples are the membrane-associated protein Annexin 11 that functions in linking large RNA granules to lysosomal vesicles during mRNA transport in axons and dendrites (Liao et al ., 2019).…”

“…This process is evolutionarily conserved in fungi, plants, and animals (Baumann et al ., 2012; Cioni et al ., 2019; Tian et al ., 2020a; Liao et al ., 2019; Müntjes et al. , 2021; Quentin et al ., 2021; Schuhmacher et al ., 2021). In endosperm cells of developing rice seeds, cargo mRNAs are transported to the cortical endoplasmic reticulum ER by the action of the two RNA recognition motif (RRM)-containing proteins RBP-P and RBP-L.…”

“…Annexin 11, a factor implicated in amyotrophic lateral sclerosis (ALS), was found as an mRNP linker on motile lysosomal vesicles (Liao et al ., 2019). Also, the five-membered FERRY complex was recently identified connecting mRNAs encoding mitochondrial proteins to neuronal endosomes by interaction with the active form of Rab5 (Quentin et al ., 2021; Schuhmacher et al ., 2021).…”

“…Transport endosomes are important carriers that move messenger ribonucleoprotein complexes (mRNPs), consisting of RNA-binding proteins and cargo mRNAs on their cytoplasmic surface (Mofatteh & Bullock, 2017;Müntjes et al, 2021;Niessing et al, 2018). This process is evolutionarily conserved in fungi, plants, and animals (Baumann et al, 2012;Cioni et al, 2019;Tian et al, 2020a;Liao et al, 2019;Müntjes et al., 2021;Quentin et al, 2021;Schuhmacher et al, 2021). In endosperm cells of developing rice seeds, cargo mRNAs are transported to the cortical endoplasmic reticulum ER by the action of the two RNA recognition motif (RRM)-containing proteins RBP-P and RBP-L.…”

Linking transport and translation of mRNAs with endosomes and mitochondria

“…Expressing these mutant alleles resulted in highly elongated mitochondria and altered mitochondrial membrane potential indicating a functional influence on mitochondrial morphology and bioenergetics. Intriguingly, a novel link between endosomes, RNA and mitochondrial biology has been recently discovered studying the novel Rab5a effector complex FERRY (preprint: Quentin et al, 2021;preprint: Schuhmacher et al, 2021;Fig 2C). Co-purification experiments using the FERRY complex as molecular handle revealed the presence of mRNAs and ribosomal proteins on endosomes suggesting a role in endosome-coupled transport and translation of mRNAs (preprint: Schuhmacher et al, 2021).…”