New Research Reveals Protein Complex FERRY’s Role in mRNA Transport in Brain Cells

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

Using a cryogenic electron microscope, they showed the structure of FERRY and how it binds to the mRNA. These findings may deepen our understanding of neurological disorders caused by failed mRNA transfer.

Key Facts:

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

source: Institut Max Planck

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

Far, so close!

“This publication provides major advances in elucidating the mechanisms underlying mRNA distribution in brain cells,” said Marino Zerial. The cell produces 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 several centimeters across the brain.

“This means thousands of mRNAs have to be transported far from the nucleus, much like the logistical effort to properly supply supermarkets across countries,” said Jan Schumacher, the study’s first author.

Until recently, researchers associated the role of transporters with spherical compartments within cells, called latent endosomes. However, MPI scientists think that different compartmental forms, called early endosomes (EEs), are also suitable as mRNA carriers, because of their ability to travel in both directions along a network of intracellular pathways.

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

Within the neuron, FERRY binds to the EE and acts similarly to a connecting belt during transmission: it directly interacts with the mRNA and carries it to the EE, which then becomes the logistic carrier for mRNA transport and distribution into brain cells.

Intricate details

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

In a second publication, Denise Quentin et al. cryo-electron microscopy (cryo-EM) was used to deduce the structure of FERRY and the molecular features that allow the compound to bind to EE and mRNA.

FERRY’s new 3D atomic model, at 4 Ångstrom resolution, demonstrates a new RNA binding mode, which includes the coil-coil domain. Scientists have also shed light on how certain genetic mutations affect FERRY’s ability to bind to mRNA causing 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 relevant therapeutic targets,” said Raunser.

About this genetics and neuroscience news

author: Johann Jarzombek
source: Institut Max Planck
communication: Johann Jarzombek – Institut Max Planck
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

summary

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

Highlight

• Ferry binds the mRNA to the early endosome in long-distance transport of the transcript
• The unique synapse-like structure of the pentameric FERRY Rab5 effector complex
• The complex RNA-binding interface mainly includes the flexible coil-coil domain of Fy-2
• Mutations associated with neuronal disorders impair Rab5 and FERRY aggregation

summary

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

Here, we define a human cryo-EM architecture. This reveals a unique synapse-like structure unlike any known Rab effector structure.

A combination of functional and mutational studies revealed that while the Fy-2 C coil-terminal serves as a binding site for Fy-1/3 and Rab5, both coils and Fy-5 are amenable to mRNA binding.

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

Our study provides mechanistic insight 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 the coil-coil domain.