Cytochrome
c (cyt
c) is a stable globular protein which functions in a monomeric state as an electron donor for cytochrome
c oxidase. It is also released to the cytosol when permeabilization of the mitochondrial outer membrane occurs at the early stage of apoptosis. For half a century, it has been known that cyt
c forms polymers, but the polymerization mechanism remains unknown. In the crystal structures of dimeric and trimeric cyt
c, the C-terminal helices are replaced by the corresponding domain of other cyt
c molecules and Met80 is dissociated from the heme. The solution structures of dimeric, trimeric, and tetrameric cyt
c were linear based on small-angle X-ray scattering measurements, where the trimeric linear structure shifted toward the cyclic structure by addition of PEG and (NH
4)
2HPO
4. The absorption and CD spectra of high order oligomers (∼40 mer) were similar to those of dimeric and trimeric cyt
c but different from those of monomeric cyt
c. These results show that cyt
c forms polymers by successive domain swapping, where the C-terminal helix is displaced from its original position in the monomer and Met-heme coordination is perturbed significantly. Successive domain swapping may be a common mechanism of protein polymerization.
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