Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which is involved in the early stages of complex IV assembly

ABSTRACT: Cytochrome c oxidase assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here we show that the absence of COA7 leads to arrest of the complex IV assembly pathway after the initial step where the COX1 module is built, progression from which requires the incorporation of copper, through the biogenesis of the CuA site. The crystal structure of COA7, determined to 2.4 Å resolution, reveals a ‘banana-shaped’ molecule composed of five helix-turn-helix repeats, tethered by disulfide bonds. We find that in solution, purified COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 that function in copper delivery to COX2 and catalyzes the reduction of disulfide bonds within these proteins, which constitute the protein copper binding sites. We therefore propose that COA7 is a heme-binding disulfide reductase that acts in the biogenesis of the CuA site, that underpins complex IV assembly.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Exploris 480, LTQ Orbitrap Elite, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: David Stroud  

LAB HEAD: David Stroud

PROVIDER: PXD031589 | Pride | 2022-03-23

REPOSITORIES: Pride