The heme molecule is an obligatory cofactor in the terminal enzyme complex of the electron transport chain, cytochrome oxidase. Heme is synthesized from heme by a multi-spanning inner membrane protein, heme synthase (Cox15 in the yeast). The insertion of heme is critical for cytochrome oxidase function and assembly, but this process has not been fully elucidated. To improve our understanding of heme insertion into cytochrome oxidase, here we investigated the protein-protein interactions that involve Cox15 in In addition to observing Cox15 in homooligomeric complexes, we found that a portion of Cox15 also associates with the mitochondrial respiratory supercomplexes. When supercomplex formation was abolished, as in the case of stalled cytochrome or cytochrome oxidase assembly, Cox15 maintained an interaction with select proteins from both respiratory complexes. In the case of stalled cytochrome assembly, Cox15 interacted with the late-assembling cytochrome oxidase subunit, Cox13. When cytochrome oxidase assembly was stalled, Cox15 unexpectedly maintained its interaction with the cytochrome protein, Cor1. Our results indicate that Cox15 and Cor1 continue to interact in the cytochrome dimer even in the absence of supercomplexes orwhen the supercomplexes are destabilized. These findings reveal that Cox15 not only associates with respiratory supercomplexes, but also interacts with the cytochrome dimer even in the absence of cytochrome oxidase.
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