Disturbance at the Protein Factory
Large update of the ribosome
[ribosome background image]
[ribosome background graphic]
While our ribosomes do some frameshifting naturally, it’s also a strategy used by viruses, like HIV, to take control of the cells they occupy. "They Hijack the Ribosomes," he says.

There is nothing new about scanner technology. It's been built into living cells for eons.

In every cell, thousands of microscopic “scanners” called ribosomes are constantly latching onto strips of ribonucleic acid, RNA, to read the coded recipes and manufacture the proteins that are essential to keep cells functioning and healthy. But ribosomes also can become unwitting accomplices to diseases.

University of Missouri biochemist Peter Cornish has spent his budding career investigating how ribosomes read the cells’ RNA code and how viruses, which have RNA of their own, hijack ribosomes in order to reproduce. His goal is to open a new front on the war against disease by finding drugs that will thwart viruses’ attempts to take control of ribosomes. He’s also looking for ways to shut down the ribosomes in bacteria and cancer cells to keep them from proliferating.

“I always liked to solve problems,” Cornish says. “A ribosome is a big black box.”

A transplant from Texas to the Midwest, Cornish, just 35, has impressed the scientific community with his ribosome research. His work has been published in the Proceedings of the National Academy of Sciences, Science, Molecular Cell and the Journal of Molecular Biology.

This year, he was among 22 scientists named a Pew Scholar in Biomedical Sciences, and he received a National Science Foundation CAREER award in recognition of his work. The Pew honor, which includes a $240,000 prize, goes to promising young investigators. The National Science Foundation award comes with a five-year $789,000 grant that will pay for the work of two graduate students. He will also hold a week-long workshop for high school students and teachers next year to teach them about his work.

Cornish calls ribosomes “dynamic machines.” Each ribosome is a “macromolecular complex” of about 50 proteins and three chains of RNA; each ribosome has two main sections, one larger than the other. “It’s one of the few components (of a cell) you can see with an electron microscope,” Cornish says.

There are thousands of ribosomes in each cell — a single E. coli bacterium will have about 15,000. Human cells have similar numbers.

Ribosomes are working constantly to interpret the messages from the genes that make up the codebook in the cell’s nucleus. Each gene is composed of two strips of nucleic acid— deoxyribonucleic acid, DNA&Mdash;locked together like a twisted zipper, the famous double helix. Before that code can be read, the DNA helix has to unzip so that a strand of messenger RNA, mRNA, can be produced. It’s the mRNA that gets scanned by the ribosomes.

DNA code is in a four-letter alphabet – A, T, G, C – standing for adenine, thymine, guanine and cytosine. The “words” of this code, called codons, are all three letters long.

It takes two to six of these words to order up one of the 20 amino acids that go into making proteins. For example, a CAA and a CAG code for the amino acid, glutamine; AGA and AGG code for arginine.

Strands of RNA from the cell’s nucleus may attract a multitude of ribosomes that latch on to read different portions of the chain.

The RNA runs like a computer tape between the larger and smaller sections of the ribosome, contacting mostly the smaller part. As the code is read, the amino acids and proteins are produced. In a single human cell, ribosomes — sometimes called the body’s protein factories — are producing more than a million amino acids every second to form thousands of protein molecules.

Scientists have known about ribosomes since the mid-1950s, but it has taken awhile for them to crack into these “black boxes.”

“We’ve known for a long time there were two main subunits to a ribosome, but we thought that it was solid,” Cornish says. Only in recent years, using X-ray imaging, has the true structure of ribosomes has been revealed. “The ribosome has all these proteins stuck on its edges,” Cornish says. They look something like decorations on a Christmas tree.

The decoding done within the ribosome is handled by its own dedicated strands of RNA, called transfer RNA (tRNA). So why are there so many proteins attached to ribosomes? It may be how they evolved.

“The idea that some people have is that RNA was the original molecule and the proteins came on to stabilize the structure,” Cornish says.

Indeed, X-ray diffraction images of ribosomes suggest that the proteins serve as “spot welds” to hold the RNA in place.

These new findings also suggest an answer to a question that has long stumped evolutionary biologists.

A half-century ago, scientists were able to put a primordial atmosphere of methane and ammonia in a flask, bombard it with electricity and create amino acids. But the next step of combining amino acids into proteins has been puzzling because a watery environment keeps amino acids from linking together as proteins. There are no water or proteins inside a ribosome: it’s the ribosome’s RNA that acts as a catalyst to synthesize the proteins from the amino acids.

Cornish’s research has shown how a ribosome actually moves along the mRNA as it scans the code. It reaches out with its tRNA to the messenger RNA, grabs hold and then releases it in a rotating motion that sends it farther down the mRNA strand.

“It’s like pulling itself down a rope,” he says.

Cornish uses a technique called Förster resonance energy transfer (FRET) to discern the movements within a ribosome. Laser light beamed at one molecule is picked up by another nearby molecule. The amount of energy that’s transferred can be measured to determine how far apart the molecules are.

Cornish’s laboratory for doing such studies looks like something designed by Rube Goldberg and a mad optometrist. There is a table filled with an assortment of lenses and mirrors used to bend and focus laser beams for the total internal reflection microscope he uses to view the motion of single molecules. “We’re not just taking snapshots; we’re watching it in real time,” Cornish says.

Ribosomes read mRNA three letters – one codon – at a time. Along the mRNA are “start” and “stop” codons that tell the ribosome when to begin scanning the code and when it’s made enough of the protein.

There are also “frameshifting signals” that tell the ribosome to change how it scans the letter code. Instead of reading three letters and moving on to the next three, the ribosome may be told to move backwards one letter.

These signals may appear as kinks in the messenger RNA, like knots in a piece of string that put tension on a ribosome as it scans the code and cause it to shift. For example, in a sequence of G GGA AAC, instead of going from GGA to AAC, the ribosome may read GGA and then shift backwards to GGG. “If you’re not going plus three each time, you’re changing the message,” Cornish says. “That has implications.” While our ribosomes do some frameshifting naturally, it’s also a strategy used by viruses, like HIV, to take control of the cells they occupy. “They hijack the ribosomes,” he says.

The ribosome will make a protein but may not read the stop codon, so it goes on to make another protein that the virus wants. And ribosomes may mistake viral messenger RNA for the cell’s own RNA and become a manufacturing plant for the virus.

Cornish is trying to find out why frameshifting occurs and what RNA structures lead to frameshifting. Such insights could lead to drugs that disable the viruses. “If we can disrupt or eliminate frameshifting in viral messenger RNA, we can prevent it from making proteins and propagating,” he says.

Drugs aimed at frameshifting may have a significant advantage over other strategies for anti-viral medications: Cornish thinks viruses may be slower to develop resistance to them.

Cornish’s theory is that because frameshifting is such a vital issue to the survival of cells, there has to be a strong interplay between ribosomes and RNA. That may mean that frameshifting isn’t as open to mutation as other cellular functions. For that to happen, both RNA and ribosome would need to mutate together for the cells to keep working. And ribosomes are so big, and use so much energy, it would be hard for successful mutations to occur.

This, in turn, implies that viruses wouldn’t be able to mutate as quickly or as easily to get around a drug that interferes with frameshifting. Another possibility for drug therapy would be to inactivate or slow down the ribosomes in cells. That would keep pathogens like bacteria from reproducing. This tactic also could be used against cancer cells, which proliferate quickly, but could be stopped if they didn’t get the proteins that they needed fast enough.

Cornish is using FRET technology to look for potential drugs that stop the motion of ribosomes along messenger RNA, or that keep frameshifting from occurring. These molecules would bind to ribosomes. “It would basically be a new class of drugs,” he says.

Although he was born and raised in Texas, Cornish doesn’t have the slightest trace of a Lone Star state accent. He attributes that to having parents from up north — his mother is from Philadelphia and his father from CanadA&Mdash; and to having grown up near the large and cosmopolitan city of Houston.

The lanky redhead played basketball in high school, but science and math were his true interests. His father was a chemist, so Cornish grew up exposed to more than his share of science. When it came time for school science projects, he says, “Dad usually helped me a lot with those.”

Cornish went to his parents’ alma mater, Graceland University in Iowa, where he majored in biology, chemistry and math. In was there he started dating Erin, his future wife. For graduate school, Cornish wanted to be back in Texas, so after graduating from Graceland in 2000, he headed to Texas A&M to study biochemistry.

“I liked biology, chemistry and math. I assumed there would be some math in it, so that’s what I wanted to do,” he recalls.

Cornish didn’t know what research he would pursue at Texas A&M until he started working with a member of the faculty on the structure of one of the kinks in RNA, called a pseudo-knot, that cause ribosome frame shifts. He found ribosomes were a challenging and worthy puzzle.

Cornish didn’t necessarily intend to continue working on ribosomes past graduate school but, one might say, working with genetic material seemed to be part of his DNA. As a post-doc at the University of Illinois at Urbana–Champaign, he began looking at the way ribosomes move. He came to MU in 2010 and began teaching in the fall of 2011.

Cornish and his wife now have three children, a son, 7, and daughters, 4 and 1. The kids occupy a lot of Cornish’s free time. “They’re certainly more challenging than working with graduate students,” he says.

The rest of the time, Cornish usually can be found in the classroom or in his lab. “I’m still an assistant professor. I have to get tenure,” he says.

And there’s still plenty more to learn about ribosomes. “We know more than we did, but it’s still a black box.”

Reader Comments

PEIWU QIN wrote on March 26, 2013

That is super cool.

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