Aggie scientists explore the world of protein folding and its significance
Published: Wednesday, January 26, 2005
Updated: Wednesday, July 25, 2012 23:07
The scene is all too familiar. A parent opens the door to a messy room with clothes strewn about and yells at the sulking teen, "Clean up your room ... and fold up those clothes!" Understandably, the teen is not very motivated by such a mundane task.
In fact, we rarely give folding more than a second thought. At the microscopic level, though, folding takes on a whole new meaning. A team of A&M scientists, led by biochemistry professors James Sacchettini and Ry Young, report on a protein that can transform from a molecular bystander to a chemical bulldozer by changing the way it is folded. Their results were published in the Jan. 7 issue of the journal Science.
Our bodies are made up of different types of cells, which are themselves made up of different types of molecules. Some of the molecules, called proteins, are linear chains of different chemical blocks called amino acids and the true workhorses of the biochemical world.
A snake-like chain of amino acids without a distinct shape is virtually useless. Therefore, a protein must fold into a varying three-dimensional shape to function properly. This holds true in all life forms, from complex humans to bacteria made of only one tiny cell.
Nick Pace, professor of biochemistry at A&M, studies protein folding. He is one of many scientists trying to solve the "protein folding problem."
"Protein folding means being able to predict the three-dimensional structure of a protein," Pace said.
Correct folding is important, Pace said, because "many diseases are protein folding diseases," including Alzheimer's disease, Huntington's disease and cystic fibrosis. In these diseases, incorrect folding of important proteins causes the disease's symptoms.
Think of protein folding as biochemical origami - a bland chemical chain masterfully folded into an elegant and efficient protein machine.
Theoretically, the specific order of amino acids should determine the three-dimensional shape of the protein, just like a sheet of paper able to fold itself into an elegant origami swan.
The study by Sacchettini and Young demonstrates how protein folding can be unexpectedly complex.
Not a protein folding scientist by trade, Young studies bacteriophages (phages, for short), which are viruses acting as molecular parasites that infect bacterial cells.
Young says his work is important primarily because "it increases our understanding of how bacteriophages destroy bacterial cells." He said, "there is a coming medical revolution where bacteriophages are going to be used as medicines because we are running short on antibiotics" due to bacteria becoming increasingly resistant to them.
"(The phages') natural job is to destroy bacteria," Young said. "That's what they do for a living."
It may seem strange that phages would destroy their bacterial host, which they are completely dependent on, but after a phage infects a bacterial cell it reproduces itself rapidly, and its progeny must escape from their bacterial womb, killing the bacterial cell in the process.
A bacterial cell is protected by two layers: a weak and flexible membrane surrounded by a strong and rigid cell wall. The phage that Young studies uses the protein Lyz, a molecular time bomb that must not become active until needed, to break through the bacterial cell wall.
When phages produce Lyz inside of a bacterial cell, it accumulates in an inactive form in the bacterial membrane, due to the way it is folded.
When needed, Young said, Lyz "goes through a dramatic change in shape and changes its chemical bonding pattern." This new active form destroys the cell wall, releasing the imprisoned phages into a world ripe with new bacterial cells to attack.
"It's unprecedented for a protein to undergo this kind of change," Young said.
In addition to Young and Sacchettini, the other authors of this study are Min Xu, Arockiasamy Arulandu, Douglas Struck and Stephanie Swanson, an undergraduate student.
Sacchettini and his research group do not predict the shapes of proteins. They determine their actual structures using a process called X-ray crystallography. Arulandu, Swanson and Sacchettini determined the structures of the inactive and active forms of Lyz.
Swanson, a senior genetics major said that predicting protein structure is difficult, and their study "blows those (prediction) methods away." She said that computer prediction methods could not have shown them the detailed change they saw in the actual Lyz structures.
When asked about the "protein-folding problem," Swanson said Lyz "probably complicates the picture... this protein is very unique."
In theory, protein folding is simple. Proteins are subject to the same physical laws as anything else. If one could understand the forces involved in protein folding, predicting the structure of new proteins should be fairly simple.
"It just turns out," Pace said, "that the physics involved in protein folding is a lot more complicated than we thought it would be."
Pace said that while most experiments have been performed on proteins in isolation, "inside the cell protein folding is a lot more complicated" because of the presence of other proteins.
Pace is optimistic, and said "we know quite a bit about the mechanism of protein folding ... There are probably at least two Nobel Prizes left for the person who can solve the protein folding problem."