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David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell@scripps.edu Website: http://www.scripps.edu/pub/goodsell
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Cytochrome c is at the very heart of life in our oxygen-rich world, but at the same time, it is a skeleton key opening the door to death. Cytochrome c, shown in Figure 1, is an ancient protein, developed early in the evolution of life. Its essential function(s) have ensured that it has changed little in millions of years. You can look into yeast cells or plant cells and find molecules of cytochrome c that are nearly indistinguishable from our own.
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P: T1 [4 K5 P1 b( u F( G2 q5 HFigure 1. Cytochrome c is a carrier of electrons. Like many proteins that carry electrons, a prosthetic group directly handles the electrons. Cytochrome c contains a heme group with an iron ion at the center that accepts and releases electrons easily. The surrounding protein tunes the affinity of the iron ion for electrons, and also directs the docking of cytochrome c to the two protein complexes that supply and receive the electrons. Atomic coordinates were taken from entry 3cyt at the Protein Data Bank (www.pdb.org).
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' n9 s# | g) i: R k' {The familiar function of cytochrome c, taught in every biology class, is its role as a carrier of electrons. It is a small, mobile molecule that shuttles electrons through the last step of aerobic energy production. These electrons are obtained from the glucose that we break down for energy, they are shuttled through a series of proton pumping proteins, and they are placed finally on oxygen, which combines with hydrogen ions to form water. Cytochrome c shuttles these electrons in the narrow space between the two mitochondrial membranes. It diffuses from protein to protein, picking up electrons from one huge membrane-bound complex and placing them at their final destination on another.1 a* f, m% l1 Z0 l% @0 E! U# G
; ]$ `; |3 g% @6 l& R' dBut cytochrome c has a darker side as well. As shown in Figure 2, cytochrome c and the mitochondria play a central role in apoptosis, signaling the cell to begin the process of programmed cell death. Apoptosis is triggered when something is amiss with the cell: DNA damage, detachment from neighbors, growth factor deprivations, infection, or a host of other signs. The cell then initiates one or more cascades of signaling proteins that spread the message through the cell and ultimately orchestrate a controlled self-destruction. Apoptosis is essential in many natural processes, such as the coordinated growth and selective pruning that shapes a growing embryo. If the system is corrupted, however, the consequences are dire, leading to degenerative diseases if overactive and allowing the growth of cancers if blocked.$ S7 C$ x+ [7 i# ^6 o8 Y( y
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Figure 2. Cytochrome c in apoptosis. A cross-section of the edge of a mitochondrion is shown at the top in green, with two membranes. The inner membrane is folded and filled with the many large protein complexes that perform aerobic energy production. The outer membrane, running through the center of the picture, has been perforated by the apoptotic protein Bax, shown in purple. This allows cytochrome c, in bright red, to escape into the cytoplasm at the bottom. There, cytochrome c associates with the Apaf-1 to form the seven-armed apoptosome. This complex finally activates the protein-cutting caspases that begin the heavy work of cell death.
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Surprisingly, this type of "moonlighting" is fairly common for proteins. Some proteins, like cytochrome c, have one function in one place and an entirely different function in another place. For instance, the enzyme phosphoglycerate kinase also moonlights as a signaling molecule: it performs the second step of glycolysis inside the cell, but outside the cell it is a cytokine controlling growth and differentiation. Diverse proteins have specific biochemical functions in the cytoplasm, but are also used for sheer bulk to fill up the glassy cells of the eye lens. Evolution is opportunistic, continually pressing its existing machinery into additional service.
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) r1 m# U! A2 K3 ]1 Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003;15:691–699.
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2 Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol 2000;10:369–377.
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0 f; \; |* e z3 Jeffery CJ. Moonlighting proteins. Trends Biochem Sci 1999;24:8–11.(David S. Goodsell) |
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