Rear-end collision on the 'ribosome highway'
Researchers identify bacterial protein that senses and rescues 'stalled' ribosomes

Date:
March 10, 2022
Source:
Heidelberg University
Summary:
As a molecular machine found in the cells of all organisms, the
ribosome is responsible for making new proteins. For a number
of reasons, this process can fail, leaving the ribosome stalled
on the mRNA and bringing synthesis of the protein to a halt. An
international research team has now identified a bacterial protein
called MutS2 that senses and rescues these stuck protein factories.



FULL STORY ==========================================================================
As a molecular machine found in the cells of all organisms, the ribosome
is responsible for making new proteins. It reads the blueprint for a
certain protein on a messenger molecule - known as messenger RNA (mRNA)
- and then converts this information into new proteins. For a number
of reasons, this process can fail, leaving the ribosome stalled on the
mRNA and bringing synthesis of the protein to a halt. An international
research team led by scientists from the Center for Molecular Biology
of Heidelberg University (ZMBH) has now identified a bacterial protein
called MutS2 that senses and rescues these stuck protein factories. The
fact that the next ribosome on the mRNA chain collides with the stalled ribosome plays a key role.


==========================================================================
The blueprints of proteins are stored in the DNA in the cell nucleus,
where they are transcribed into mRNA. Bearing the genetic information for
a specific protein, the mRNA leaves the nucleus and is transported to the ribosomes, where its information is converted into proteins. "Sometimes ribosomes can get stuck reading the blueprints owing to a defective
mRNA molecule, for instance. This is particularly problematic because unfinished proteins are potentially toxic to the cell," explains ZMBH
molecular biologist and working group leader Prof.

Dr Claudio Joazeiro. "That is why cells have developed mechanisms that
detect stalled ribosomes and mark the incomplete proteins for destruction
while still in their birthplace, the ribosome." Using high-resolution cryo-electron microscopy, the researchers decoded a major step in this
process with the aid of the common soil bacterium, Bacillus subtilis. They
were able to precisely characterise how the MutS2 protein, found in
nearly one third of all bacteria species, senses stalled ribosomes. MutS2 detects the collision between the stuck ribosome and the next one on
the mRNA - a process which ZMBH junior research group leader Dr Stefan
Pfeffer likens to a rear-end collision caused by a stalled vehicle on
the highway, thus catching the attention of the police.

To rescue ribosomes stuck on the mRNA, MutS2 follows two independent strategies, according to the researchers. "On one hand, MutS2 cuts the
mRNA molecule, which subjects it to degradation. On the other hand, MutS2 separates the ribosome into its two subunits, so that it can be recycled
for later rounds of protein synthesis. At the same time, the so-called ribosome-associated protein quality control marks the unfinished protein
for destruction," explains Dr Pfeffer. Prof. Joazeiro emphasises that this quality control mechanism is conserved from bacteria to humans. "We thus
expect that the understanding of this fundamental process in bacteria
will shed light on disease mechanisms in mammals, where failure to
degrade unfinished proteins is associated with neurodegeneration and neuromuscular diseases," adds the researcher.

In addition to the ZMBH researchers from Heidelberg, scientists from
the University of Cologne as well as Scripps Research in Florida (USA)
also participated in the study. Funding was provided by the US National Institute of Neurological Disorders and Stroke, the German Research
Foundation, the European Union in the context of "Horizon 2020", the
Aventis Foundation and the Chica and Heinz Schaller Foundation. The
results of the study were published in the journal Nature.


========================================================================== Story Source: Materials provided by Heidelberg_University. Note: Content
may be edited for style and length.


========================================================================== Related Multimedia:
* Cryo-EM_structure_of_the_collided_ribosomes_with_MutS2 ========================================================================== Journal Reference:
1. Federico Cerullo, Sebastian Filbeck, Pratik Rajendra Patil, Hao-Chih
Hung, Haifei Xu, Julia Vornberger, Florian W. Hofer, Jaro Schmitt,
Guenter Kramer, Bernd Bukau, Kay Hofmann, Stefan Pfeffer, Claudio
A. P.

Joazeiro. Bacterial ribosome collision sensing by a MutS DNA repair
ATPase paralogue. Nature, 2022; DOI: 10.1038/s41586-022-04487-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220310115041.htm

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