|The Last Piece of the Puzzle
CHORI Scientist Proves Flexible FAS Structure
The February issue of Nature Structural and Molecular Biology features on its cover an exciting new study by CHORI scientist Stuart Smith, PhD and his colleagues from the Scripps Research Institute, Edward Brignole, PhD and Francisco Asturias, PhD, that solves the last remaining questions about the structure of fatty acid synthase (FAS), the fat-making enzyme that plays a key role in energy metabolism.
“The crystal structure of FAS solved last year by a team of Swiss researchers marked a major breakthrough in our understanding of the architecture of this remarkable complex but, nevertheless, left open several questions,” says Dr. Smith, who has been pioneering FAS research for more than two decades.
“The main issue that remained unclear was how enzyme components that appeared to be distantly located in the crystal structure could make the functional contact required to produce the biochemical data on FAS that had already been experimentally demonstrated.”
The structure of FAS has been a conundrum in protein chemistry for years, primarily because the protein is so large, containing all the enzymes for fatty acid biosynthesis, in which water soluble molecules are turned into fat. The protein has attracted considerable attention in recent years, however, as it appears to have great potential as a target for development of new anti-cancer and anti-obesity agents.
Over the last 15 years, the Smith lab has produced a substantial amount of biochemical data, much of which, however, was at odds with the traditional FAS textbook model. While the crystal structure solved by the Swiss group confirmed a great deal of this data, it still wasn't enough to put the question of the FAS structure to rest."While X-ray crystallography can generate a high-resolution protein structure, it is essentially a static image, providing a snapshot of the protein in only one particular conformation," explains Dr. Smith.
"There was just no way we could have anticipated such a dramatic motion," Dr. Smith says. "This enzyme is able to flip back and forth so incredibly rapidly, in the span of a few milliseconds. It's quite astonishing that it requires that much internal flexibility in order to fulfill its catalytic role."
In addition to establishing such revolutionary flexibility, the results of the study also resolve - in Dr. Smith's favor - once and for all the longstanding controversy over FAS structure and function.
"Once we had subjected our data to rigorous analysis and convinced ourselves of the validity of our results, we realized that we could now formulate a dynamic model for the FAS that was consistent with both the X-ray crystal structure and all of our biochemical data," explains Dr. Smith. "It resolves all of the remaining issues as to how FAS functions, and how FAS flexibility facilitates all of the interactions between its domains."
Tuesday, May 17, 2011 8:19 AM