Delving into RNA function

06-09-2022

New results on RNA regulation give insight into how the cell discards disruptive RNA transcripts that could lead to diseases. This research is a great example of collaboration of the IBS, EMBL and ESRF within the Partnership for Structural Biology (PSB). Their findings are published in Nature Communications.  

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Ribonucleic acid (RNA) is an essential molecule in coding, decoding, regulation and expression of genes. Together with DNA, they are nucleic acids, which represent one of the four major macromolecules essential for life.

An astonishing amount of RNA is constantly being synthesized within eukaryotic nuclei in the cells. There are some aberrant RNA transcripts of the genes, which can lead to diseases if not discarded from the RNA.

 To detect and eliminate these aberrant transcripts, cells rely on highly regulated RNA degradation machineries. Unwanted transcripts are recognized by specialized RNA-targeting complexes that deliver them to the nuclear molecular machinery called RNA exosome for degradation. Any disruptions in RNA degradation can have dramatic consequences for human health, including cancer and neurodegeneration. The yeast MTREC (Mtl1-Red1 core) protein complex and its human counterpart PAXT are essential regulators of this RNA surveillance.

The subunit composition of the yeast MTREC and human PAXT complexes has been previously characterised by proteomics. However, until now there was no 3D structural information available on the interactions that MTREC forms with the individual sub-modules. Similarly, the function of these modules in MTREC/PAXT activity still remained unclear.

Now, a team led by the Institut de Biologie Structurale in Grenoble has found the biochemistry and structural analysis of two important interactions of Red1 with MTREC sub-modules, combined with in vivo studies.

The Molecular Biology Lab of the ESRF, which is dedicated to molecular biology and biochemistry for structural analyses, played an important role in the discovery. “We carried out a specific assay in the lab to understand how the sub-modules interact with each other”, explains Montse Soler López, head of the structural biology group at the ESRF. “With this assay we obtained crucial insights about the complex architecture of the MTREC/PAXT molecule and unveiled the interaction and self-association of the different parts of the molecule”, she adds.

The crystallography analysis was done at the beamline ID30A-3, where they solved the crystal structure of one the most interesting identified complexes, called Ars2-Red1 complex. “The ESRF played an important role in this research, not only on the beamline but also in the Molecular Biology Lab of the ESRF, which allowed us to determine exactly which complexes we wanted to characterize”, explains Jan Kadlec, team leader at IBS and corresponding author of the publication. “This shows how working together within the PSB on campus can lead to revealing results”, he concludes.

The results provide structural insights into the MTREC architecture orchestrated around the dimeric Red1 scaffold. These structural features occur in both the yeast and the human complex, which indicates they both use the same mechanism to control RNA metabolism. The next step for the team is to characterise larger complexes with additional MTREC subunits and target RNA to obtain detail understanding of the nuclear RNA degradation mechanism.

Reference:

Foucher, AE., et al. Structural analysis of Red1 as a conserved scaffold of the RNA-targeting MTREC/PAXT complex. Nat Commun 13, 4969 (2022). https://doi.org/10.1038/s41467-022-32542-3

Text Montserrat Capellas Espuny

Top image: Crystal structure of the Ars2-Red1 complex. Credits: Jan Kadlec