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School of Medicine
February 2009--In 1971, a group of students gathered on a field at Stanford University to perform an unusual interpretive dance. Their subject: protein translation.
As video cameras rolled, students played the roles of different molecules. A long chain of students holding hands represented the messenger RNA that carries the genetic instructions for producing a protein. Two clumps of tumbling and leaping students played the role of the ribosome, the machine that reads the code. Other dancers enacted the part of transfer RNA, the molecule that delivers to the ribosome the amino acids that correspond to the mRNA code. Finally, a lengthening line of dancers, each representing an amino acid, emerged from the cluster of performers— the growing protein chain. (A video of the performance, definitely worth watching, can be seen on YouTube under protein synthesis.)
What the dancers lacked in sophistication they made up for in enthusiasm. Their exuberance reflected the heady mood of a period in molecular biology when scientists were harvesting an abundance of information about basic biological processes such as protein translation.
Decades later, it is now clear that the first explanation of protein translation, remarkable as it was, revealed only a broad outline of the process, says Jon Lorsch, an associate professor of biophysics and biophysical chemistry. During the past 30- plus years, biologists have elucidated many more details and discovered other players that take part in the performance. Several key pieces of that work have emerged from the Hopkins labs of Lorsch and Rachel Green, a professor of molecular biology and genetics.
Lorsch has focused on the initiation phase of protein translation. A ribosome attaches to one end of a strand of messenger RNA and begins traveling down the strand searching for the position where it must begin decoding the genetic message to translate the code into protein. Scientists have known for many years that this “start codon” is the nucleotide triplet AUG. They have also identified 24 initiation factors required for this first step. But many other details remain undefined.
“Imagine you have a parts list,” says Lorsch. “But you don’t really know how the parts fit together and know only vaguely what each part does.”
Lorsch has spent the past several years defining the role of one of those parts, an initiation factor called eIF1. This factor, he says, acts as a sort of “master switch” of initiation. eIF1 at first is associated with the ribosome as it travels down the mRNA strand. When the ribosome arrives at the start codon, eIF1 is ejected, Lorsch discovered. The release of eIF1 somehow throws a switch, telling the ribosome to put on the brakes and prepare to begin decoding the message. “I’m captivated by the incredible complexity of this system,” says Lorsch.
But what if that system makes a mistake? asks Green. Suppose, for instance, a ribosome links the wrong amino acid into the polypeptide chain. Such mistakes can result in a misshapen protein and have been found to contribute to neurodegenerative diseases.
Green recently discovered a proofreading step that the ribosome appears to use to prevent such errors. Working with bacterial ribosomes, Green and postdoc Hani Zaher created conditions that forced the protein translation machinery to make mistakes.
When a mistake happens, she found, protein production quickly comes to a halt, and the amino acid chain is released. “To our astonishment, we found the ribosome seemed to know that the protein being synthesized was not quite right,” says Green, who published her findings in the January issue of Nature. “The system recognized the subtle defect.”
As they continue to learn the details of protein synthesis, the Hopkins researchers are also starting to explore how they might exploit the mechanism to find new methods of treating diseases such as cancer. Many anticancer drugs target DNA replication, says Lorsch. Another strategy, disrupting protein translation, he says, “is an under-explored area of cancer treatment.” In his lab, he is currently screening tens of thousands of compounds to find candidates for this task.
In separate research, Professor of Pharmacology Jun Liu is studying a natural compound that may be such an agent. Several years ago, Liu came across a study showing that the New Zealand marine sponge Mycale contained a compound with potent tumor killing properties. Intrigued, Liubegan his own investigation and discovered that the compound inhibits protein translation. He is now continuing those studies in animal models, research he hopes will lead to clinical studies and new cancer drugs.
Even as they pursue medical applications, the basic “how does- it-work” questions remain the most inspiring, says Lorsch. For instance, if eIF1 is like the master switch of protein translation’s initiation phase, what throws the switch? One day, says Lorsch, he’d like to be able to answer such questions by actually observing protein translation in action, perhaps through fluorescence microscopy.
There are still more nuances of this dance to discover.
Rachel Green contemplates her fascination with the ribosome