Howard Hughes Medical Institute 2010 Annual Report

HHMI investigator Thomas A. Steitz An artist’s illustration of the ribosome

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A Roadmap to the Ribosome

Weighing in at more than 150,000 atoms, the ribosome is the engine of life itself, a delightfully intricate cellular gizmo that executes the last piece of the central dogma of biology: information is transferred from DNA to RNA to protein. The ribosome transforms RNA into the proteins that brick-by-biological-brick build bacteria, birds, and biochemists.

With the right equipment and an inventive research team, HHMI investigator Thomas A. Steitz described the ribosome’s molecular structure in fine detail. And he shared the 2009 Nobel Prize in Chemistry for his efforts.

As Steitz’s map helped show, the ribosome reaches back to the very beginning of cellular life on Earth, some two billion years ago. Describing its shape afforded a glimpse into that almost-unknowable past while offering a roadmap to the future of antibiotics.

In 1986, when HHMI launched a program to fund top structural biologists, Steitz was one of the first chosen. At the time, the National Institutes of Health rarely bought equipment for its grantees. But with HHMI support, Steitz invested in x-ray equipment and a million dollar computer. Both proved crucial.

The investment was “almost immediately transformational,” Steitz says. With the new equipment, he marched through the central dogma, solving protein structures at a pace never before seen in structural biology.

An Irresistible Challenge

At 10 times the size of the biggest molecule anyone had ever solved, the ribosome demanded special treatment. So Steitz and his colleagues—Yale biochemist Peter Moore and postdoctoral fellow Nenad Ban—were pressed to invent new x-ray crystallography techniques. In a crucial triumph, the Yale team learned how to add clusters of heavy atoms to the ribosome crystals and locate their positions. The heavy atoms produced a big x-ray signal that acted as a waypoint, or landmark, in the mapping process.

As the team generated the first low-resolution images of the ribosome, they double-checked their data against images made by HHMI investigator Joachim Frank. Though fuzzy by x-ray crystallography standards, Frank’s electron microscopy images offered proof that the Yale team’s techniques were, in fact, working.

Steitz and his collaborators drove on. In 1998, they published their first ribosome paper, a low-resolution map of the large ribosomal subunit—the factory half of the machine, the part that actually builds proteins. (The other half, the small subunit, is the foreman—it receives messenger RNA and ensures delivery of the correct amino acid for the large subunit to add to the growing protein chain.)

The team revealed their methods, and the race was on as other researchers adopted them.

Within a year, the Yale team sharpened the image threefold. They made a trip to the powerful x-ray beam at Argonne National Laboratory in Illinois for final data collection. As information poured in, the scientists spent months interpreting it, placing nearly every atom by hand. By early 2000, they completed a finely wrought 2.4-angstrom-resolution structure of the large ribosomal subunit.

“It was extraordinary,” says Steitz. “We had no idea what the ribosome was going to look like at that level of detail.”

RNA World

Some 31 proteins glued together the outer shell and helped with housekeeping tasks. But deep inside, where the protein-making magic happened, there was nothing but coiled RNA, 3,000 bases of it. Here, laid bare, was a revelation about the secret of life: proteins are not built by other proteins, as some biologists once assumed. RNA does the job. Ribosome researchers had speculated about this possibility for decades—starting with Francis Crick in 1968—but the Yale structure proved it.

The implications were profound: the ribosome map provided robust support for the theory that the first organisms on Earth were built from RNA. “The ribosome is a prime basis for the ‘RNA world’ hypothesis” of how life began, says former HHMI President Thomas Cech.

And while the ribosomal shell differs from organism to organism, the RNA center, where the protein-building action happens, is nearly identical across every species on the planet. For some two billion years of cellular evolution, the heart of the machine has been there churning out proteins, building life.

Fortunately, minute differences exist between bacterial and human ribosomes. Antibiotics exploit these differences, damaging bacterial ribosomes to kill the bacteria.

Steitz’s lab continues its work on the ribosome, determining the structures of the assembly bound to various antibiotics. And he continues directing a high-throughput operation that has unraveled the structure—and hence, the function—of dozens of proteins as well as ribosomes from different species.

“When you look at what Tom has contributed to the fundamental understanding of information transfer in organisms, it's just enormous,” says Peter Moore, Steitz’s longtime friend and colleague. “The ribosome is the capstone, but it’s by no means his only big contribution.”

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Photo Credit: Paul Fetters