How systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors
Getting a fix on when and where mistakes occur in the cellular manufacture of proteins is a challenge that many had a crack at. It took an extensive interdisciplinary collaboration across four labs (Weizmann Institute, CRI at INSERM/University of Paris, Max Planck Institutes and Tel-Aviv University) to accomplish this formidable mission. They found out that the genomic DNA contains a “mistake manual” of sorts, that dictates where these mistakes need to be avoided at all costs, and where they may be tolerated or even welcomed.
Errors in protein production occur most of the time in the ribosomes
In a recent study appeared in Molecular Cell, Prof. Yitzhak Pilpel (head of the Molecular Genetics Department at the Weizmann Institute of Science), Dr. Ariel Lindner (research director at INSERM and CRI co-founder at the Université de Paris), Prof. Tamar Geiger (Tel-Aviv University) and collaborators  , analysed and quantified errors in entire proteomes. They revealed that errors in protein production can originate from spelling mistakes in the DNA itself, but most commonly occur in the ribosome at the final stage of protein production, known as “translation.”Wrong amino acids are inserted at this stage into a protein at the average rate of one in about 1,000 amino acids – that is, almost one mistake per protein. But the range is great: from one mistake in several dozen amino acids to one in about 10,000.
A mechanistic basis of ribosome errors
Mapping out the late-stage mistakes has until now been nearly impossible because all analyses yielded average numbers for all of the protein building blocks. We were able to signal the presence of errors but not where on the protein those errors had occurred. The project addressed this challenge by applying advanced algorithms to data obtained with a mass spectrometry method recently developed for studying individual substitutions of amino acids in a protein. The researchers then tested this approach on rapidly dividing yeast and bacterial cells.
They found out that the distribution of these mistakes is far from random. Mistakes are much more common in proteins expressed in the cell in smaller than in larger amounts. This is probably because the latter, more abundant proteins would clutter up the cell much sooner should they contain errors, so that the cell would not have survived in the course of evolution.
Moreover, within each protein, translation errors are much more common at positions that are less critical to the protein’s function and stability than at the more crucial ones, for example, those sites responsible for binding to other molecules. Globally, mistakes are ‘allowed’ in positions where they are expected to be minimally detrimental, but not in the more sensitive positions. But how does the ribosome know when it’s “allowed” to make mistakes ?
The study results suggest that the rate of mistakes at this stage is at least partially preprogrammed, and that such preprogramming might be achieved through the genetic regulation of translation speed. In fact, the scientists found an inverse correlation between translation speed and accuracy : the faster the ribosome turned out proteins, the more errors it made. Conversely, it appeared to be programmed to slow down when accuracy was essential, as if it was taking its time in order to do things right.
A new direction for multitude research topics
In a new study, the researchers also found that mistakes in translation can be triggered by external conditions : when they exposed dividing cells to an antibiotic, the rate of these mistakes increased. It might help establish whether translation mistakes play a role in the evolution of species by creating diverse proteins that may help the organism adapt to changing conditions.
All these findings could open up new directions of research. For example, further studies could examine, the role of translation mistakes in Alzheimer’s and other neurodegenerative diseases. Other studies could also determine whether these mistakes slow down or accelerate cancerous growth, or whether they speed up the aging process.