How Mutations Change Proteins

Mutations in genes can be dangerous because they often cause changes in several levels of protein structure. The situation is a bit like the well-known parable from Benjamin Franklin: "For the want of a nail, the shoe was lost; for the want of a shoe, the horse was lost; and for the want of a horse, the rider was lost, being overtaken and slain by the enemy, all for the want of care about a horseshoe nail."

Altering one letter of DNA often leads to a change in one amino acid letter in the primary structure of a protein. This may change the close-range attractions between amino acids, which in turn can alter the formation of alpha helices and beta sheets (secondary structure), disrupting the shapes of domains (tertiary structure) and changing the set of other molecules that the protein can bind to. The effect is like putting a part designed for one type of car into the wrong model. If it does not fit, the part may break, possibly destroying the engine and even the whole automobile. A defective protein shape can break a molecular machine, and it may even kill the whole cell.

In the 1990s a number of studies by Peter T. Landsbury, a structural biologist at Harvard Medical School, Christopher Dobson of the University of Leeds, and other labs showed that different types of mutations can have similar effects on protein structure by transforming alpha helices into beta strands, then sheets, and finally tight clumps that the body cannot break down again. Such clumps were first found by the German physician Alois Alzheimer (1864-1915) in the brain of a woman who had died after suffering from a progressive disease that destroyed her mind. He found that dense amyloid fibers—made mostly of beta sheets—had collected between nerve cells in the brain, linked to the death of the cells and the symptoms of Alzheimer's disease. Since then fiber-forming proteins have been connected to about 20 different neurodegenerative diseases. These molecules and the diseases they cause will reappear as an important theme in chapter 5.

An entire field called structural biology is devoted to the study of the architecture of proteins and other molecules. One im

portant application of this work is the discovery and refinement of new types of drugs. The active ingredients of medicine are usually small molecules that work by docking onto proteins and changing their shapes and activities. For example, the surface of a protein may have a hole that has to be filled by a small molecule in order to be activated. If a drug plugs up the hole, that cannot happen.

This is why aspirin works. The drug had been used since 1899, when the Bayer company began to market it worldwide. But how it functioned was a mystery until 1971. That year John Robert Vane (1927-2004), a researcher at the Royal College of Surgeons in London, discovered that it prevents the production of fat molecules called prostaglandins by blocking sites in proteins called COX-1 and COX-2. The discovery earned Vane the 1982 Nobel Prize in physiology or medicine, along with the

Swedish biochemists Sune K. Bergstrom (1916-2004) and Bengt I. Samuelsson (1934- ), for other key discoveries about the activity of prostaglandins.

By studying the map of a protein, structural biologists can discover the exact locations where molecules dock onto each other and determine what features a drug would have to have to interfere with a protein's activity. But to do so they need a three-dimensional structure of the molecule, which is difficult to obtain. As it is much easier to discover a molecule's sequence, structural biologists would like to learn to predict what secondary, tertiary, and quaternary structures a protein will form based on its amino acid spelling. Then it would be possible to plan and make artificial molecules shaped in a precise way, designed to control the behavior of other molecules. It might also be possible to see how a mutation would affect a protein's structure and behavior.

It is now possible to design small molecules with specific shapes, but scientists have not yet worked out the rules by which larger molecules achieve their folds. Some proteins contain thousands of amino acids, each of which is potentially able to bind to many others. The number of potential folds in a single molecule is so large that even today's largest computers are unable to calculate which ones will be produced by the chemical forces of all the amino acids. But it may be possible to find shortcuts, which is an area of intense research. In fact, every two years the U.S. National Institutes of Health sponsors an Internet competition based on this theme. Laboratories across the world are given a string of amino acids and use their computer programs to predict what shape it will form. The results have to be calculated purely by computer within two days. The winner in 2006 was Yang Zhang, an assistant professor at the University of Kansas. His entry was closest to the real shape—but still far from the structural biologist's dream of creating a detailed map of a complex molecule based on the sequence alone.

Protein structures are a good example of how strings of chemical subunits shape molecules and direct their behavior. DNA and RNA are made of different subunits, nucleotides, but the same basic principles of chemistry determine how they function. Their structures will be discussed in the next chapter.

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