SANTA CRUZ, CA — The workings of a tiny molecular machine crucial to all forms of life are emerging from highly detailed new images obtained by researchers at the University of California, Santa Cruz. In a paper published by the journal Science on March 30, the researchers describe the structure of the ribosome, a complex particle just one millionth of an inch in diameter, in sufficient detail to begin to understand how it works.
"This allows us to see what all the key parts are and how they interact," said Harry Noller, Sinsheimer Professor of Molecular Biology and head of the group that obtained the new images.
Ribosomes are the protein factories of all living cells. They hold the equipment necessary to read the genetic code and translate it into specific protein structures. Inside every cell, tens of thousands of ribosomes churn out proteins with mind-boggling speed and precision. They are ancient structures that show little variation among different forms of life. Most research has focused on bacterial ribosomes, which are composed of three different RNA molecules and more than 50 different proteins arranged in two major subunits.
One of the most striking features of ribosomes is that the components that carry out protein synthesis are made of RNA, a type of molecule similar in structure to DNA. In contrast, the enzymes that catalyze most of the chemical reactions necessary for life are proteins. The central role of RNA in the function of the ribosome is an idea long championed by Noller and others, but only recently confirmed by a series of landmark studies by Noller’s group at UC Santa Cruz and by other researchers, including Peter Moore and Thomas Steitz of Yale University. In April, the three researchers will share the prestigious Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science in recognition of this important discovery. The new paper provides further confirmation that ribosomal RNA is the active component in protein synthesis.
"Why these ancient organelles use RNA, instead of protein, for the complex and biologically crucial task of protein synthesis is a fascinating question, the answer to which may shed light on the origins of life on Earth," Noller said.
Noller and his coworkers published the first detailed images of a complete ribosome in 1999. In their new paper, the three-dimensional structure of the ribosome is revealed in much finer detail, enabling them to identify specific components that carry out key functions. The lead authors of the study are Marat Yusupov and Gulnara Yusupova, visiting researchers at UCSC’s Center for Molecular Biology of RNA, now at the French national research center in Strasbourg. The coauthors, in addition to Noller, are Albion Baucom and Kate Lieberman at UCSC; Thomas Earnest at Lawrence Berkeley National Laboratory; and Jamie Cate, now at the Whitehead Institute in Cambridge, MA.
Biologists have known the basic outlines of protein synthesis for decades. The instructions for making a protein are carried to the ribosome by a messenger RNA molecule, which has copied the instructions from chromosomal DNA, the storehouse of genetic information carried in almost every cell. The building blocks of proteins are carried to the ribosome by transfer RNA molecules. On the ribosome, the transfer RNAs recognize specific sequences of genetic code on the messenger RNA and line up the protein building blocks in the proper order. The ribosome then catalyzes the formation of chemical bonds between the building blocks.
The images obtained by Noller’s group show not only the ribosome itself but also messenger RNA and transfer RNAs in the positions they occupy during the process of protein synthesis. Most of the action involved in protein synthesis seems to take place at the interface between the two ribosomal subunits. Noller and his coworkers identified 12 chemical bridges linking the two subunits, mostly involving ribosomal RNA. They also located the sites where the ribosome interacts with the transfer RNAs. These findings enabled them to propose mechanisms by which protein synthesis is coupled with movements of specific components of the ribosome.
"The ribosome is a molecular machine, and it must have moving parts to accomplish its function. We are now in a position to understand the structural rearrangements of the ribosome during protein synthesis," Noller said.
This achievement has practical significance because many antibiotics work by binding to and disrupting bacterial ribosomes. Understanding the ribosome’s structure may lead to the development new and more effective antibiotics.
The images were obtained using a technique called x-ray crystallography. The improved resolution of these new images is the result of fine-tuning some two dozen variables in the group’s experiments, Noller said. The ribosome is the largest molecular structure ever solved by x-ray crystallography.
University Of California, Santa Cruz. April 2001.