Ride-on binding: the mRNA transport system has been uncovered in brain cells

summary: Researchers have made major advances in understanding how mRNA is distributed in brain cells. They discovered that a protein complex called FERRY helps early endosomes (EEs) to transport mRNAs to distant parts of neurons.

Using cryogenic electron microscopy, they showed the structure of FERRY and how it binds to mRNAs. These findings could deepen our understanding of neurological disorders caused by failure of mRNA transfer.

Key facts:

1. Discovered by MPI scientists, the protein complex, FERRY, has been identified as a critical component of mRNA transmission within brain cells.
2. Previously underestimated, early endosomes (EEs) play a pivotal role in mRNA distribution by acting as mRNA transporters, with the help of FERRY.
3. Using cryoelectron microscopy, the researchers revealed the complex structure of FERRY and its novel RNA-binding pathway that is implicated in certain neurological disorders.

source: Max Planck Institute

Teams from the MPI institutes in Dresden, Dortmund, Frankfurt am Main and Göttingen join forces to obtain the first evidence of a protein complex involved in the transmission of messenger RNA in neurons..

Far, so close!

“These publications provide a major advance in elucidating the mechanisms underlying mRNA distribution in brain cells,” says Marino Zerial. Cells produce vital proteins using mRNA as a blueprint and ribosomes as 3D printers.

However, brain cells have a logistical challenge to overcome: a tree-like shape with branches that can extend for centimeters in the brain.

“This means that thousands of mRNAs would have to be transported far from the nucleus, something like a logistical effort to properly supply supermarkets in an entire country,” says Jan Schumacher, first author of the study.

Until now, researchers have attributed the role of the transporter to spherical compartments within the cell, called latent endosomes. However, MPI scientists argue that a different form of compartments, called early endosomes (EEs), are also suitable as mRNA carriers, due to their ability to travel in both directions along intracellular road networks.

In the first publication, led by Marino Zerial from MPI in Dresden, the scientists discovered the function of a protein complex they named FERRY (five endosomal Rab5 subunits and RNA/ribosome intermediarY).

In neurons, FERRY binds to EEs and acts similar to a connecting belt during transmission: it directly interacts with mRNA and carries it onto EEs, which thus become logistical carriers for mRNA transport and distribution into brain cells.

Intricate details

But how does FERRY relate to mRNA? That’s when Stefan Raunser’s kit from MPI Dortmund came into play.

In the second publication, Denise Quentin et al. cryo-electron microscopy (cryo-EM) was used to infer FERRY’s structure and molecular features that allow the compound to bind to both EEs and mRNAs.

FERRY’s new 3D atomic model, at a resolution of 4 Ångstroms, shows a novel RNA-binding mode, which includes coiled-coil domains. Scientists have also explained how certain genetic mutations affect FERRY’s ability to bind mRNA leading to neurological disorders.

“Our research lays the foundation for a more comprehensive understanding of neurological disorders caused by failure of mRNA transport or distribution, which may also lead to the identification of therapeutically relevant targets,” Raunser says.

About this genetics and neuroscience news

author: Johann Jarzombek
source: Max Planck Institute
communication: Johann Jarzombek – Max Planck Institute
picture: Image credited to Neuroscience News

Original search: open access.
“Structural basis for mRNA binding by the human FERRY Rab5 effector complexBy Stephan Raunser et al. molecular cell

a summary

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

Highlights

• Ferry binds mRNA to early endosomes in the long-range transport of transcripts
• Unique synapse-like structure of the pentameric FERRY Rab5 effector complex
• The complex RNA-binding interface mainly includes the flexible coiled-coil domains of Fy-2
• Mutations associated with neuronal disorder impair Rab5 and FERRY pooling

summary

The FERRY Rab5 pentase effector complex is a molecular link between mRNA and early endosomes in intracellular mRNA distribution.

Here, we define the human cryo-EM architecture. It reveals a unique synapse-like structure unlike any known structure of Rab effectors.

A combination of functional and mutational studies reveal that while the Fy-2 C-terminal coiled-coil serves as a binding region for Fy-1/3 and Rab5, both the coiled-coil and Fy-5 agree to bind mRNA.

Mutations that cause Fy-2 truncation in patients with neurological disorders impair Rab5 binding or FERRY complex assembly. Thus, Fy-2 acts as a binding hub that connects all five complex subunits and mediates mRNA binding and early internalization via Rab5.

Our study provides mechanistic insights into long-distance mRNA transport and demonstrates that the special structure of FERRY is closely related to a previously undescribed mode of RNA binding, which includes coiled-coil domains.