JUPITER, FL – September 7, 2017 – The devil, as always, is in the details. The production of proteins is a complex process, made up of a series of smaller intricate biochemical steps that succeeds because of an equally complex number of quality controls. Without them, the process would irreparably break down and diseases like cancer would run rampant.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown for the first time that the assembly of the cellular factories that produce proteins, the basic working units of any cell, also involves quality control steps.
The study, which was published September 7 online ahead of print in the journal Molecular Cell, was led by Katrin Karbstein, an associate professor in the Department of Integrative Structural and Computational Biology.
“With important cellular machines like ribosomes, it makes sense that mechanisms exist to make sure things work correctly,” Karbstein said. “We’ve confirmed for the first time that such a quality control function exists for these small ribosomal subunits that, in essence, do a test run but don’t produce a protein – without it, mistakes in RNA translation would produce dangerous mutated proteins.”
Ribosomes, which are large macromolecular machines required for cell growth in all organisms, catalyze the production of proteins in all cells. They read the genetic code carried by messenger RNA (mRNA), and then catalyze or translate that code into proteins within cells, assembling them from amino acids.
Understanding the process of ribosome assembly—which involves almost 200 essential proteins known as “assembly factors” in addition to the four RNA molecules and 78 ribosomal proteins that are part of the mature ribosome—is a potentially fruitful area of research because of the importance of ribosome assembly for cell growth.
“We used genetic and biochemical experiments to show that bypassing this step in translation-like cycle produces defects,” said Homa Ghalei, the first author of the study. “Our results show that this cycle is a quality control mechanism that ensures the fidelity of the cellular ribosome pool.”
The link between defects in ribosome assembly and cancer clearly points to this pathway as a new target for anti-cancer drugs. Ribosomes are the targets of many commercially used antibiotics and represent a promising area of research because of the importance of ribosome assembly and function for cell growth.
“We now understand how this complicated assembly process works and we can finally show that this really is a quality control mechanism – a significant advance over a discovery we made back in 2012, which we were never able to prove,” Karbstein said. “But even then, it seemed to be the most logical conclusion.”
The subunits in question are known as 40S ribosomal subunits that bind to other subunits to produce larger ribosomes – called 80S-like ribosomes because they do not produce any proteins.
In addition to Karbstein and Ghalei, other authors of the study, “The ATPase Fap7 Tests the Ability to Carry Out Translocation-like Conformational Changes and Releases Dim1 during 40S Ribosome Maturation,” are Juliette Trepreau, Jason C. Collins, Hari Bhaskaran, and Bethany S. Strunk, all of TSRI.
The study was supported by the National Institutes of Health (Grant R01-GM086451), the Howard Hughes Medical Institute and PGA National Gold Club.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see www.scripps.edu.
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