MAR 24, 2019 11:45 AM PDT

Cryptic Start Sites in the Bacterial Genome Can Generate 'Alternative' Proteins

WRITTEN BY: Carmen Leitch

It has been thought that one gene sequence codes for one protein (though the cellular machinery can make variations of that protein through a variety of mechanisms) as described in the video. Now research in bacteria has shown that a gene can potentially code for several different proteins. The work was performed by researchers at the University of Illinois at Chicago (UIC), who used an antibiotic to reveal the expression of what they call an alternative proteome. It has been reported in Molecular Cell
 

The genome is made up of a series of nucleotide bases, and the cellular machinery reads them in sets of three. Those nucleotide triplets, or codons, code for amino acids, which compose the proteins that make an organism. The same codon signals the beginning of every gene, the so-called start codon or start site. 

In this work, the researchers developed a technique that found every start codon in a bacterium in one experiment. In doing so, the scientists showed that one gene can code for multiple proteins; there were start sites inside of gene reading frames, which could initiate the synthesis of other proteins that were both in- and out-of-frame. They also found that some genes have multiple start sites. 

The scientists used a topical antibiotic called retapamulin. It works, they found, by stalling the cell’s protein-making at start sites.

"First, we understood the antibiotic's mechanism, and then we applied that knowledge to identify the special 'start' gene signals the cell uses to regulate protein synthesis," said Alexander Mankin, the Alexander Neyfahk Professor of Medicinal Chemistry and Pharmacognosy at the UIC College of Pharmacy. "In the past, these start codons were identified by rather difficult processes; proteins often needed to be isolated and studied to discover where the start sites of their genes are located in the bacterial genome. Now, in a single experiment, we can profile the starts of all the thousands of bacterial genes in a more forward manner."

Led by Mankin and Nora Vázquez-Laslop, the team exposed Escherichia coli bacteria to retapamulin. The identified over 100 bacterial genes in a genome of about 4,000 that can begin to make proteins at multiple sites; these proteins had cryptic start sites.

Caption: A digitally-colorized, scanning electron microscopic (SEM) image depicts a dividing, Escherichia coli bacterium at 21674X / Credit: CDC/ Evangeline Sowers, Janice Haney Carr

"We saw that many previously hidden proteins were initiated at sites in the middle of the gene and that those proteins were functional and that initiation at alternative start sites is widespread in bacteria," explained Vázquez-Laslop, research professor of medicinal chemistry and pharmacognosy at the UIC College of Pharmacy and the Center for Biomolecular Sciences.

"Proteins initiated at these unknown sites may constitute a previously hidden fraction of the proteome - the entire set of proteins that can be expressed - in bacteria and their initiation at these sites may play a role in the life of the cell," said Mankin, who is also director of the Center for Biomolecular Science. "By better understanding the cell and the mechanisms of antibiotic action, we can apply that knowledge to learn more about what makes bacteria become pathogenic."

"We can also apply that knowledge to better understand how to prevent or stop bacteria from causing harm," Vázquez-Laslop added.


Sources: Phys.org via University of Illinois at Chicago, Molecular Cell

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