The Many Faces of Heme

In what is considered by some a startling discovery, John Shelnutt at the Department of Energy's Scandia National Laboratory (Albuquerque, NM) has found that heme, the iron-binding co-factor found in a variety of proteins, can take on a number of forms depending on the function of the protein. The finding that heme—assumed by most to exist solely in a simple, planar structure—can do this, and further that particular forms are linked to particular functions, could have far-reaching implications in the study of proteins structure-function relationships.

In a series of studies published last year in The Biophysical Journal and the journal Biochemistry, Shelnutt reported on an analysis of X-ray crystallographic data of some 400 crystal structures of heme-containing proteins, using a computer program developed by a postdoctoral student Walter Jentzen in his group. The program, the only one of its kind, used a mathematical procedure for characterizing the structure of hemes termed normal-coordinate structural decomposition (NSD). So far, Shelnutt has identified some 70 different heme shape variations (called distortions), of which he has determined that only six are important for hemes in proteins. Those six are saddling, ruffling, doming, propellering, and two types of waving, each named according to how the heme appears.

"Before, people always thought the heme's primary function was to simply hold the iron in the protein so that the iron could carry out some biochemical reaction," Shelnutt says. "They weren't aware that the heme acted as part of the protein 'machine' and changed shape or even had shape. Many even believed it was flat [which it is outside the protein]. We've shown that that inside the protein the heme is three-dimensional, or nonplanar, and its shape corresponds to function."

Shelnutt has also determined that distortions are specific to functions and can be found in proteins from other species, both similar and different, that perform similar tasks, suggesting that certain shapes have been conserved. "Conserved heme structures within the proteins tell us that the heme's shape plays an important role in determining the function of the protein," Shelnutt says. "We can see that different proteins may perform similar functions from the shape of the heme."

Another new concept that Shelnutt's research has revealed is that many hemes change shape and go from one distortion to another as they perform their work. For example, when a nitrogen-fixing, heme-containing protein binds with oxygen, the heme in the protein changes shape, losing its ruffling distortion. This causes the protein itself to change shape, turning off nitrogen fixation. Then, when oxygen is no longer around, the heme ruffles once again, and nitrogen fixation is switched back on.

Shelnutt is already putting his discovery into practice. In collaboration with a French scientist, he is developing new anti-inflammatory drugs. Another possible application could be in cleaning up toxic waste. Once it is understood how the heme in one protein facilitates the conversion of sulfites or nitrites, common pollutants, into hydrogen sulfide or ammonia, analogous structures of hemes could be chemically engineered, produced in large batches, and released to clean up waste sites.

For more information: Chris Burroughs, Sandia National Laboratories, 1515 Eubank SE, Albuquerque, NM 87123. Tel: 505-844-0948. Or contact: John Shelnutt, Sandia National Laboratories. Tel: 505-272-7160.