Biochemists know when to fold ’em

U of T biochemists have made history by using a magnetic field 200‚000 times stronger than that of the Earth to catch a glimpse of life in action. Dr. Lewis Kay and his post–doctoral fellow Dmitry Korzhnev‚ with the publication of their study in the prestigious journal Nature‚ became the first scientists to describe the structure of an unfinished protein.

Proteins‚ the molecular machines that all life depends on‚ are first created as long‚ thin strands of material‚ which are then folded into complex structures‚ like a piece of string being tied into a complicated knot. Scientists know a great deal about proteins‚ but they still don’t understand how this folding works. This missing information is very important‚ not just for understanding how biology works‚ but for understanding human illness. Many diseases result from proteins not folding properly‚ including Alzheimer’s‚ cystic fibrosis‚ and plaque formation.

“If you understood what the misfolded proteins looked like‚ you could add a drug that would stabilize the folded form‚” says Kay. At some point along the pathway of folding‚ an error occurs‚ sending the protein along the wrong fork in a road. “If you can reroute things by adding a roadblock‚ your drug‚ you can force the correct structure.”

Every action in your body—the movement of a muscle‚ creation of sperm‚ conversion of sugar into energy‚ intake of oxygen—relies on proteins. When your body needs to create a certain protein‚ say keratin‚ contained in your hair and nails‚ or hemoglobin‚ the substance in your red blood cells that sticks to oxygen‚ it reads your DNA for instructions on how to make that protein. Your DNA is like a cookbook‚ a set of instructions for how to make a living thing‚ and a gene is simply a small stretch of DNA‚ the specific recipe for a certain protein.

Proteins are made up of about 20 simple building blocks‚ called amino acids. After reading the gene for instructions‚ the cell creates a long strand of amino acids linked together. Each protein has a different sequence of these building blocks‚ which can run anywhere from hundreds to tens of thousands of amino acids. This long strand then folds through a complicated process into a 3D structure‚ the finished protein. Some proteins are shaped like spirals‚ others like flat sheets‚ others like globular blobs‚ it depends on what the protein is used for.

But scientists have never been able to understand exactly how proteins go from these simple strands into complex shapes. Some sections of the strand fold before others‚ some parts fold into each other‚ some parts don’t fold at all; it’s extremely complicated. Even if scientists know what the series of amino acids in a protein is‚ which is easier now that the human genome has been sequenced‚ they still don’t know what the actual finished protein looks like.

Understanding the folding process is extremely difficult however‚ because proteins fold so quickly that the intermediate states‚ the semi–folded proteins‚ are very hard to find in a cell. Kay and his team used a method called NMR spectroscopy to try and uncover the secrets of these elusive molecules. By subjecting a sample of a specific protein to an incredibly powerful magnetic force‚ they were able to look at what happens when the rare‚ partially folded proteins change into folded ones‚ and through mathematical calculations get a rough picture of what the partially finished protein looks like.

Although he now works in the science of life‚ Kay received his Ph.D. in physical chemistry. “Working on biological molecules is fun‚ you almost always learn something‚ and there’s always questions in biology that nobody has the foggiest idea about‚” he said. “Physicists and chemists deal with smaller systems‚ say four atoms [at a time]. But at the end of the day‚ we live in a world with people‚ and big molecules…so you’d like to do something a little more relevant.”