LONG ISLAND, NEW YORK—After an evening that touched on Darwin and the evolution of fish, ants, and humans, the "Evolution: The Molecular Landscape" symposium at Cold Spring Harbor Laboratory was true to its title and headed into the RNA world first thing the next morning. Or rather, the ribonucleoprotein world. Ribonucleoproteins (RNPs) are complexes of RNA and proteins. Many researchers are convinced that the first life depended on RNA and that proteins came later. Those proteins eventually squeezed out RNA from most of its roles carrying out the molecular processes needed for survival. But proteins—or at least simple peptides—were likely in the mix from the very beginning, said Thomas Cech of the University of Colorado, Boulder. He added that "it was never an RNA world." Moreover, it's not just a protein world today. There is increasing appreciation for the amount of RNA transcribed from the genome that doesn't code for proteins. Thus, in partnership with proteins, RNA continues to figure largely in cellular function. A look at RNPs shows that there is a give-and-take between the two partners in the roles they play in the complex.
The discovery of the first ribozymes—RNA enzymes—in 1982 had provided a way out of the chicken-and-egg problem of which came first, proteins or nucleic acids, such as RNA, because today both types of molecules are critical to life. Life started with RNA, then proteins and DNA came along later and outdid RNA as arbiters of biological reactions and information carriers, respectively. Ribozymes evolved into RNPs, which gradually lost their RNA components to produce modern protein enzymes (see diagram). But "we don't see RNA disappearing," Cech said. Instead, it's proved surprisingly versatile.
Cech argues that the same abiotic conditions that favored the formation of nucleic acids likely also favored small peptides. On its own, RNA is so-so as a catalyst, but in RNPs, it continues to play a vital role. The same synergy likely existed in those earliest days, he says.
Take the ribosome. "They are the Trojan horses that came out of the RNA world," said Venki Ramakrishnan of the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom. Every molecule in the cell is made by the ribosome or by a protein produced by the ribosome. Over the past decade, he and others have worked out that the RNA subunits are at the core, controlling the assembly of amino acids into specific proteins. Its protein partners help hold two RNA subunits in a semirigid structure that shifts back and forth to pull in amino acids and push out the emerging protein chain.
The rigidity of the ribosome is a sharp contrast to telomerase, which was found to be an RNP in 1987. Telomerase typically consists of one RNA and several protein subunits, including a reverse transcriptase protein called TERT that extends the ends of replicated chromosomes to keep them from getting shorter each time they are copied. The RNA specifies the bases that TERT adds. But Cech's group has found that RNA also acts as a flexible scaffold that recruits other proteins, such as a DNA repair protein called Ku. When they alter the RNA so that it doesn't bind Ku, telomerase doesn't work as well. When they add an extra binding site on the RNA for Ku, then chromosomes grow extra-long, he said. The RNA's arms are flexible and swing into different positions. Yet in the lab, Cech's crew has shortened these arms without affecting the RNP's function. "It's a dynamic system where proteins can switch in and out," says Cech.
Both the ribosome and the telomerase show signs that the protein-RNA partnership is dynamic over evolutionary time as well. Cech and his colleagues have discovered that there is a part of the telomerase RNA that helps speed telomerase activity. "He's finding new functionality in the RNA," says Susan Lindquist of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. "A new region has come in and contributes to catalysis."
In the ribosome's case, proteins are lending the helping hand. Ramakrishnan reported the discovery of an arm of one of the ribosomal proteins that extends deep into the RNA where transfer RNAs bind and deliver amino acids. Now instead of depending on RNA alone, "protein tentacles are assisting the process," says Ramakrishnan. In mitochondrial ribosomes, proteins have taken on an ever-larger role. The ratio of RNA to protein in the cell's ribosomes is 2 to 1; but in mitochondrial ribosomes, the ratio is roughly 1 to 2. This ribosome looks about the same, but most RNAs have been replaced by protein, leaving just a small RNA core.
These examples show that RNPs "are not decaying," says Lindquist. "They are continuing to evolve."
Illustration credit: Harold White, University of Delaware