Proteins are chain molecules assembled from amino acids. The precise sequence of the twenty different types of amino acids in a protein chain is what determines which structure a protein folds into. The three-dimensional structures in turn specify the functions of proteins, which range from the transport of oxygen in our blood, to the conversion of energy in our muscles, and the strengthening of our hair. During evolution, the protein sequences encoded in our DNA have been optimised for these functions.

Understanding how proteins fold could lead to the design of new proteins for highly specific functions, or new therapeutic drugs.

Researchers Susan Marqusee and Carlos Bustamante decided to investigate this problem one protein at a time.

Grabbing both ends of a single protein, they pulled and slowly unbent the protein, then gradually let it relax into its original 3-D shape.

Research appearing in the Oct. 8 issue of the Journal of Molecular Biology, describes a new technique that may help scientists predict which proteins are prone to misfold and at what point the folding process is likely to break down. The research could support efforts to find the causes for diseases involving amyloids, and it could prove useful for researchers studying proteins involved in even more prevalent diseases like cancer and heart disease.

"We know now that most diseases involve proteins going wrong in one of two ways," said lead researcher Cecilia Clementi, assistant professor of chemistry at Rice University. "In the first, proteins don't function correctly because they fold into the wrong shape. This is something we see in sickle-cell anemia, for instance, because of genetic flaws that cause the amino acid sequence to be incorrectly synthesized.

"The second way proteins go wrong is by not folding at all, which is what we find in diseases involving amyloids. In these situations, the misfolded proteins assemble together into macroscopic aggregates."

"What we've developed is a simple and inexpensive sensor for determining when a protein changes its conformation," said study co-author Richard N. Zare, the Marguerite Blake Wilbur Professor in Natural Science in Stanford's Department of Chemistry. According to Zare, the new sensor may eventually provide biomedical researchers a fast, affordable method for detecting antibodies and other disease-related proteins.

The familial amyloidoses, on which the researchers focused their study, are caused by various mutations to a human protein called transthyretin (TTR). These mutations render transthyretin unstable and predisposed to misfolding from a normal, safe structure into dangerous, sticky ones that glom together and form microscopic fibrils, which then cluster to form larger amyloid plaques that deposit in peripheral nerves, organs, and sometimes in the central nervous system.

Strangely, some TTR mutations cause the fibrils to target the heart, others cause the fibrils to form in the peripheral nervous system, and still others cause the fibrils to form in the gut or in the brain. In the latest issue of the journal Cell, the Scripps Research team is describing the chemical and biological basis for this tissue selectivity.

It is not only, say the scientists, that certain tissues like the brain are more susceptible to the amyloid plaques because they are specifically targeted by misfolded TTR proteins, but rather because cells that secrete proteins into these tissues are the ones that secrete the bad proteins most efficiently.

"Most of the destabilized TTR variants tend to be secreted within susceptible tissues just as efficiently as normal TTR proteins, even though they are substantially destabilized," says Scripps Research Professor Jeffery W. Kelly, Ph.D., who led the research with Scripps Research Professor William E. Balch, Ph.D. Kelly is the Lita Annenberg Hazen Professor of Chemistry, a member of The Skaggs Institute for Chemical Biology, and Vice President of Academic Affairs at The Scripps Research Institute.

"The ability of the cell to efficiently release misfolded protein provides a striking and unanticipated new view of the operation of cellular secretion pathways," says Balch, who is a professor in Scripps Research's Department of Cell Biology and the Institute for Childhood and Neglected Diseases. "These results suggest that we may be able to correct these diseases by small molecules that target fundamental rules guiding protein folding and secretory pathway function."

Amyloidosis is All in How the Protein Folds

For decades, scientists have known that proteins have the propensity to fold into a particular three-dimensional structure based on the particular sequence of amino acids the body strings together. Scientists have also known that the structure of a protein is essential for the protein's function, and that an unfolded protein may not be functional. In the last few years, they have also become increasingly aware of the danger of protein misfolding and misassembly.

"What we've developed is a simple and inexpensive sensor for determining when a protein changes its conformation," said study co-author Richard N. Zare, the Marguerite Blake Wilbur Professor in Natural Science in Stanford's Department of Chemistry. According to Zare, the new sensor may eventually provide biomedical researchers a fast, affordable method for detecting antibodies and other disease-related proteins. Acid and base

The breakthrough may pave the way to drugs that fight illnesses such as Alzheimer's, Parkinson's disease, diabetes and a host of viral infections, the scientists said.

"That's why there's so much interest in this paper," said lead researcher Junying Yuan, a professor of cell biology at Harvard University Medical School.

Her team's findings are published in the Feb. 11 issue of Science.

Almost every illness involves the death of an excessive number of body cells due to stresses from both inside and outside the cell. Biologists call one of the most potent forms of cellular stress "endoplasmic reticulum (ER) stress."

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.