For nearly half-a-century, molecular biologists have sought to solve the mystery of how proteins are synthesized and the intricacies of ribosomes — the small particles in cells on which proteins are synthesized. Two UCLA molecular biologists propose a solution in the March 21 issue of the journal Nature.
The scientists — James A. Lake, UCLA professor of molecular, cell and developmental biology, and UCLA graduate student Anne B. Simonson — show how the “factory of life” works.
“The ribosome is like a computer-driven protein factory that has been cloaked in secrecy,” Lake said. “We knew the shape of the factory, and we could see the trucks going in, but we couldn’t peer beyond the factory gate. We knew the names of the employees, but we didn’t know what they did. Now we have a hypothesis of how the employees move in and out of different rooms to get their work done, and even what they have for lunch. Our hypothesis of how protein synthesis works may be refined, but we are confident that the central parts are correct.
“Proteins are the workhorses of the cell, the molecules that make us what we are, and every protein in our body is made on a ribosome,” Lake said. “Ribosomes are central to life, and are in every living organism, from the smallest bacteria to humans.”
Why is it important to understand how ribosomes make proteins?
Each of our cells has more than 100,000 ribosomes, and solving what Lake calls “the puzzle of life” requires a much greater understanding of the ribosome’s role in protein synthesis than the broad outlines scientists have had until now. In addition, the research could lead to new antibiotics, and insights into how genes are regulated, which could lead to new treatments for a variety of diseases, Lake said.
In molecular biology, translation is the process that turns genes into proteins — the “molecules of life.” Scientists have not understood how this critical process works, but have known that it has three phases: initiation, elongation and termination, of which elongation is the key. A number of antibiotics work at the translation level.
“Elongation is the heart of protein synthesis,” Lake said, the phase in which the ribosome adds amino acids, sometimes hundreds of them.
In their Nature paper, Lake and Simonson explain the molecular details of elongation, including the location and movement of more than 10,000 atoms. In addition, they have located a novel binding site for transfer RNA (tRNA) when it enters the ribosome.
“Genes are being turned on and turned off, and transcribed and translated constantly in our cells,” Simonson said. “Learning the mechanisms of how this works is key.”
With the new knowledge, it may become possible to make modifications in parts of the translation process to suppress lethal mutations and design new proteins to counteract the defects that cause numerous diseases, Lake said.
If the ribosome is a factory, then the workers in the hard hats include tRNA and EF-Tu, a ubiquitous protein molecule that is like a large motor transporting tRNAs and amino acids. Simonson and Lake have learned how they move and function.
“EF-Tu moves to exactly where it needs to go to transport the tRNA to where it needs to be so the amino acids are close enough together to be added to the end of a growing protein chain,” Lake said. “The structure led us. The ribosome’s structure was telling us, ‘It can’t move like that, it doesn’t fit there, you have to turn it this way.’ All the times we would make mistakes, the ribosome would correct us.”
“The most exciting moment for me occurred late one night when we saw the initial binding site for tRNA before it turns,” Simonson said. “The structure of the ribosome dictated how it fit in. We looked at each other and said, ‘Wow! That’s amazing.’”
The research, which involved sophisticated computer simulation, was federally funded by grants from the National Science Foundation, the National Institutes of Health, the Department of Energy and the Astrobiology Institute.