2023-06-19 16:00:10
The protein thus helps to prevent neurodegenerative diseases
All biological processes in our cells are constantly monitored. This is also intended to prevent the accumulation, or even accumulation, of incorrect proteins. In the worst case, such “protein clumps” can trigger diseases. However, errors can occur, especially when producing new proteins. The faulty proteins then have to be eliminated from our cells. How exactly this works was not yet clear. Researchers led by F.-Ulrich Hartl at the Max Planck Institute for Biochemistry in Martinsried have now discovered a new mechanism that can initiate the targeted breakdown of defective proteins. The protein “GCN1“.
The picture shows two ribosomes (each in two parts), which move one behind the other on an mRNA to read the blueprints of the proteins. You can see the amino acid chains growing out of the upper part of the two ribosomes.
© Illustration: AdobeStock, Artur
The picture shows two ribosomes (each in two parts), which move one behind the other on an mRNA to read the blueprints of the proteins. You can see the amino acid chains growing out of the upper part of the two ribosomes.
© Illustration: AdobeStock, Artur
Ribosomes are molecular machines in our cells that make all proteins. After the genetic code of an organism on the so-called messenger RNA, mRNA for short, has been transferred, the ribosomes read the blueprints of a wide variety of proteins from this mRNA. They carefully assembled amino acid following amino acid until a long chain was formed from which a functional protein might be folded. But since nothing in life runs completely smoothly, mistakes sometimes occur in this process as well. It is possible that the ribosomes overlook the STOP signal in the blueprint and build more amino acids together than is actually necessary. Such deviant proteins can be dysfunctional or even form protein clumps, which can be a feature of various neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease.
It was discovered a few years ago that cells have the remarkable ability to recognize and eliminate faulty proteins. To decipher the underlying mechanism, the research team used the worm model organism C. elegans, as well as human cells.
“Firefighter” protein calls for breakdown
Upon closer examination of how faulty proteins are eliminated, the scientists unexpectedly found that the mRNA itself is also degraded. They suspected that the problematic mRNA was already recognized during reading by the ribosome. In this context, the researchers found a complex that was previously known to play a role in mRNA degradation. In addition, they discovered that GCN1-protein plays an important role and initiates this process.
Most mRNAs are traversed by several ribosomes at the same time, like roads by cars, and read at the same time. One can then imagine the ribosomes as two cars driving one behind the other on the same road. If the first car then brakes unexpectedly, for example because a cat jumps onto the road, the car behind may crash into it and cause an accident. The GCN1 protein then acts like the fire brigade, which is the first responder at the scene of an accident. It stabilizes and secures the scene of the accident and then calls the towing service and the street cleaners, who remove the accident vehicles and also renew the road surface if necessary. The complexes in our cells called out by the fire brigade protein break down the problematic mRNA. But how exactly does the protein recognize that an accident has happened and that an app towing service and street cleaning are needed?
“Profiling” of the fire brigade protein
Crucial insights were gained using a technique called Selective Ribosome Profiling (SeRP), which makes it possible to determine the exact position of the ribosomes on the mRNAs. The researchers looked for the location of all the ribosomes bound to a fire engine protein, regardless of whether they are still driving or have already had an accident. They discovered that the fire brigade protein always intervenes when a ribosome has produced a chain of amino acids that is too long and has exceeded its actual STOP signal. Since in this situation there are more collisions between two ribosomes, the fire brigade protein then calls for accident cleaning.
In addition, the scientists found that the GCN1–Protein is not only used when STOP signals are passed. In particular, GCN1-bound ribosomes responsible for membrane proteins and collagens were also identified in mRNAs. In-depth analysis revealed that a common trait that makes these three classes firefighter targets are so-called “non-optimal codons,” a sequence of nucleotides on the genome that function like a speed limit on the road. In addition, they found that the stabilization of the ribosome accident by the fire brigade protein GCN1 also calls molecular chaperones to the scene of the accident. Chaperones are a class of proteins that help other proteins fold correctly.
The fire brigade protein supports the healthy aging of our cells
Aging is a risk factor for various diseases. Defective proteins also become more common with age and pose a threat to an organism’s health C. elegans can shorten. In fact, such a malfunction led to more proteins accumulating and pooling in older worms, which promotes neurodegenerative diseases. In the experiments with human cell lines, the researchers were able to show that there are also impairments in the administration of the protein balance. With the results of the study, the scientists want to find a way to reduce the age-related accumulation of defective proteins in order to prevent neurodegenerative diseases such as Alzheimer’s or Parkinson’s.
Images of the model organism C. elegans, which show how the defective proteins, in which too many amino acids have been assembled, are broken down. The image on the left shows a recording during which the defective proteins (yellow) are still enriched in the organism. The picture on the right shows the organism following degradation of these proteins.
© Images: Martin Müller, MPI for Biochemistry
Images of the model organism C. elegans, which show how the defective proteins, in which too many amino acids have been assembled, are broken down. The image on the left shows a recording during which the defective proteins (yellow) are still enriched in the organism. The picture on the right shows the organism following degradation of these proteins.
© Images: Martin Müller, MPI for Biochemistry
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