The RNA has several ways to slow down the beginning steps of protein production

Paying less and getting more is not just a goal of wise consumers. Living cells, too, strive to make the most of their resources. This is particularly true when it comes to the most expensive cellular process in terms of energy expenditure: gene expression, or the translation of the genetic code into proteins. In a study reported recently in Molecular Cell, Weizmann Institute scientists reveal clever strategies by which cells minimize the cost of gene expression.

“In the course of evolution, cells that made their proteins as cheaply as possible had a tremendous survival advantage over others,” says team leader Prof. Itzhak Pilpel, of Weizmann’s Molecular Genetics Department. “In fact, we can talk about the survival of the most economically efficient.”

In the new study, graduate students Idan Frumkin, Dvir Schirman and Aviv Rotman, along with other members of Pilpel’s team, discovered a number of cellular cost-cutting strategies. One, for example, resembles a ramp meter: the device that limits the rate of traffic flow entering freeways. The molecular ramp meter regulates the work of ribosomes – cellular machines that manufacture proteins. It causes the ribosomes to start out slowly, only later picking up speed as they ride along the messenger RNA molecule, or mRNA, which carries genetic information about protein composition. This regulation optimizes protein manufacture, preventing the ribosomes from getting jammed on the mRNA, much as a freeway ramp meter optimizes the flow of vehicles.

Cells that made their proteins as cheaply as possible had a tremendous survival advantage over others

Pilpel had predicted the existence of the molecular ramp meter several years ago, but only recently got an opportunity to test his predictions experimentally. “We got a unique ‘present’: scientists in the United States designed 14,000 different versions of a gene that makes a protein called GFP,” says Pilpel. “They created these variants for an entirely different purpose, but we used them to study how variations in gene design affect the cost of protein manufacture.”

After inserting each of the 14,000 gene versions into a different bacterium in a laboratory dish, the scientists compared how much GFP the bacterial cells manufactured for each mRNA molecule. “The bacteria that made more GFP per mRNA molecule obviously made the most effective use of their resources,” explains Pilpel.

(l-r) Prof. Yitzhak Pilpel, Idan Frumkin, Dvir Schirman and Aviv Rotman (inset) discovered how cells “meter” the speed on RNA strands

The researchers then sequenced the variable portions of the 14,000 gene versions and analyzed them using a bioinformatics model. They found that indeed, just as they had predicted, the bacteria that manufactured GFP most effectively were the ones in which the gene version was equipped with a ramp meter. Their analysis actually revealed three different ramp meter mechanisms – in other words, three ways to slow down the ribosome when it starts riding on the mRNA.

Like the one on the road, the first molecular ramp meter operates at the point of entry – that is, in the initial stretch of an mRNA strand. If this portion contains a genetic sequence that calls for the use of scarce supporting molecules, the ribosome is held up until it eventually lands the required molecule, getting the green light to continue. Further down the line, the mRNA contains genetic sequences that call for the use of relatively abundant molecules, enabling the ribosome to pick up speed.

Yet another molecular ramp is created by the architecture of the mRNA molecule: When mRNA’s initial region is folded rather than loose, the fold renders navigation more difficult for the ribosome, slowing it down. Finally, the ribosome can be halted due to an increased strength of its interaction with the mRNA.

The scientists also discovered some additional strategies that render gene expression cost-effective. They then showed that the naturally occurring genes in bacteria make use of ramp meters and the other thrifty strategies they had discovered.

These findings have opened up a line of research that may provide a new angle on cancer: checking whether molecular ramp meters facilitate the uncontrolled growth of cancer cells. More immediately, the study findings may benefit biotechnology: “Installing” cellular ramp meters might help to boost the manufacture of human insulin, antibodies and other medically useful substances commonly produced in bacterial cells.

Also taking part in the study were Liron Zahavi, Ernest Mordret and Omer Asraf from Weizmann’s Molecular Genetics Department, as well as Drs. Fangfei Li, Song Wu and Sasha F. Levy of Stony Brook University.

As the ribosome creates new proteins from the RNA, it begins slowly and speeds up. Animation from the lab of Prof. Ada Yonath