Environmental Factor, November 2009, National Institute of Environmental Health Sciences
Nobel Winner Speaks at RNA Society Meeting
By Dixie Ann Sawin
Sponsored in part by NIEHS, the "Symposium on RNA Biology VIII: RNA Tool and Target" was held on October 16 and 17 at the North Carolina Biotechnology Center in the RTP. One of the highlights of the program was the talk given by the recent winner of the Nobel Prize in Chemistry, Ada Yonath, Ph.D., of the Weizmann Institute of Science, Israel. Her seminar offered insights into "The identification of the prebiotic translation apparatus within the contemporary ribosome."
The symposium was organized by the RNA Society of North Carolina. (http://www.med.unc.edu/pmbb/nc-rna-soc.html) NIEHS Principal Investigator Traci Hall, Ph.D., was co-chair of the event's organizing committee.
Ribosomes, which exist in eukaryotic and prokaryotic organisms, are the "cellular machines" that translate RNA into protein. However, eukaryotic and prokaryotic ribosomes exhibit several differences. In eukaryotic organisms, ribosomes exist either as free structures in the cytosol or bound to the endoplasmic reticulum (ER), a membrane-bound compartment within the cytoplasm.
Generally, proteins that are produced by the free ribosomes will function within the cell, while the proteins formed by ER-bound ribosomes will be exported from the cell. Eurkaryotic ribosomes usually number in the millions and are larger compared to their prokaryotic counterparts. In contrast, ribosomes from prokaryotic sources, such as bacteria and viruses, occur only as free-standing organelles and may number in the thousands.
Yonath began her talk by showing a movie depicting the motions of the ribosome that guide the entrance and exit of tRNAs from a specific tunnel within the active site of the ribosome, the peptidyl transferase center (PTC). The PTC resides in an internal architectural unit within a highly conserved symmetrical region that facilitates the ribosome's primary catalytic function of peptide bond formation and amino acid polymerization. Ribosomes can make 15-20 peptide bonds per second, with an accuracy rate of 99.99 percent.
Although differences exist between prokaryotes and eukaryotes, the universality of the symmetrical design and high conservation implies that this structure can transcend different environmental conditions and is most likely the remnant of the ancient protein biosynthetic machine, the proto-ribosome, akin to a "molecular fossil." As Yonath explained, "The chemical prebiotic process originated from an oligonucleotide... that proceeded into self-assembled dimers." Thus, small pieces of RNA could spontaneously dimerize and form the building block for the protoribosome, the pre-protoribosome.
This internal symmetry supports the hypothesis that the protoribosome further evolved by gene duplication or fusion, with later genetic optimization into two similar but not identical substrates that contribute to the catalytic and decoding properties. Yonath's work provided supporting evidence for the existence of an RNA world where the ribosome co-evolved with its substrate, prior to the contemporary one in which we live.
Ribosomes are common targets of antibiotics. If this site is highly conserved, antibiotics can bind to ribosomes in both bacteria and patients, which can cause death or side effects. Therefore, if an antibiotic targets the conserved PTC region, it is usually harmful, shows resistance and is useful only in treating cancer, and a patient's remaining quality of life is often an issue. Yonath elucidated the modes of action of over twenty different antibiotics that target the ribosome. She illuminated mechanisms of drug resistance and synergism, deciphered the structural basis for antibiotic selectivity and showed that it plays a key role in clinical usefulness and therapeutic effectiveness, thus paving the way for structure-based drug design.
Yonath shares this year's Nobel in Chemistry (http://nobelprize.org/nobel_prizes/chemistry/laureates/2009/) with two other scientists, Thomas Steitz, Ph.D., and Venkatraman Ramakrishnan, Ph.D.
(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the NIEHS Laboratory of Neurobiology Neurotoxicology Group on detail as a writer for the Environmental Factor.)