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Completing a decades old quest by biochemists and biophysicists scattered around the world, a multi-institutional team of researchers has discovered the structure of Complex II, a protein essential to the production of energy within cells.  Complex II is a generic name for one of the five proteins in the process.

This discovery is important because it increases scientists’ understanding of one of the most fundamental processes of biological systems, says Gary Cecchini, PhD, San Francisco Veterans Affairs Medical Center chief of molecular biology, UC San Francisco research biochemist, and co-principal investigator of the study.  According to Cecchini, their findings may also facilitate the development of therapies to correct defects within this essential energy production system.

Team members from the San Francisco Veterans Affairs Medical Center and the University of California, San Francisco crystallized the protein—a critical but painstaking process of trial and error that is essential to be able to view protein structure under ultra high magnification.

Once Complex II was crystallized, team members from the California Institute of Technology imaged its three-dimensional structure with a technique called X-ray crystallography.  Armed with this image, biochemists can use computer modeling to unravel the mysteries of Complex II.  The results of team’s research are published in the June 18 issue of Science.

Every human cell has its own energy source - numerous tiny power plants called mitochondria.  These mitochondria use five protein complexes (multi-protein units), collectively known as the respiratory chain, to generate most of our cells’ energy.  Basically, Complexes I through IV pass electrons to each other down the chain and eventually to an oxygen molecule.  At the same time, at least three of the complexes “pump” protons through the wall of the mitochondria, which produces a gradient of electrical energy.

At the end of the respiratory chain, Complex V uses this newly created energy to produce adenosine triphosphate (ATP).  Cells in the body use ATP for fuel by chemically breaking its bonds, which produces energy the cells need to perform their many functions.

“Now that we have a picture of Complex II, we can use this to help fill in gaps in our knowledge of how the mitochondrial respiratory chain functions.  This result also should increase our understanding of how molecular defects in the chain may produce damaging oxygen free radicals, which are thought to play a role in disease and the aging process,” says Cecchini.

Since the early 1960s, it has been known that defects within the mitochondria (mitochondrial myopathies) are associated with certain metabolic diseases.  More recently, the defects have also been linked to heart failure, aging, and a wide variety of degenerative diseases such as diabetes, Alzheimer’s, and Parkinsonism.

Complex II was first discovered in 1909 but until now its structure was not known.  It has only been in the past three years that Complexes III, IV, and part of V have been crystallized and their structures studied.  Researchers are still trying to solve the structure of Complex I and the remainder of Complex V.

Proteins appear in two forms within cells, either soluble or membrane-bound.  Soluble proteins are free floating—suspended in the cell’s cytoplasm.  Membrane-bound proteins like Complex II, on the other hand, are partially embedded in the walls of the cell or mitochondria.

Although membrane proteins comprise by mass about 15 percent of cellular protein, even today scientists have solved the structures of only a very small fraction.  The structures of membrane proteins have proven much harder to solve because they are very difficult to crystallize.  In fact, the process is so arduous that it has only been in the last ten years that any structures have been determined.

A major barrier to studying the structure of membrane proteins is that they are difficult to obtain in a pure form suitable for crystallization.  To obtain enough of the protein, the researchers turned to the E. coli bacterium, which was genetically manipulated to produce fumarate reductase in large amounts.  Fumarate reductase is closely related, and very similar to succinate dehydrogenase, which is the human Complex II.  “Our results are especially satisfying because this first picture of the structure helps support decades of research on what scientists thought Complex II would look like,” Cecchini says.

The co-principal investigator on the study is Douglas C. Rees, PhD, California Institute of Technology and the Howard Hughes Medical Institute.  The team included Cesar Luna-Chavez, BS, UCSF postgraduate researcher in biochemistry and biophysics, who is credited with crystallizing the protein, and Tina M. Iverson, MS, California Institute of Technology, who imaged the protein’s structure.

The research was funded with grants from the Department of Veterans Affairs, the National Institutes of Health, and the National Science Foundation.