Morphological Change of Cell Membrane by Interaction with Domain‐Swapped Cytochrome c Oligomers

Monomeric cyt c has been reported to bind to the mitochondrial membrane by electrostatic and hydrophobic interactions with anionic phospholipids. We have previously shown that domain‐swapped oligomeric cyt c retains the secondary structure of the monomer, and its surface possesses a larger area and more charges compared to the monomer. However, the effect of oligomerization of cyt c on cells has yet to be revealed. Herein, we investigated the interaction of oligomeric cyt c with anionic phospholipid‐containing vesicles and the outer membrane of HeLa cells. Oligomeric cyt c interacted more strongly than monomeric cyt c with anionic phospholipid‐containing vesicles and the outer membrane of HeLa cells. Oligomeric cyt c induced lateral phase separation of lipids in LUVs and GUVs, thereby leading to membrane disruption, whereas monomeric cyt c did not. Morphological changes in HeLa cells resulted from interaction with oligomeric cyt c, but little from interaction with the monomer. These results show that domain‐swapped oligomeric proteins might exhibit properties different to those of monomer in cell systems.