Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 9, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2110357119
Keywords
COA7; mitochondria; cytochrome c oxidase; heme; X-ray crystallography
Categories
Funding
- Australian Research Council [DP140102746, FT180100397, DP220102030]
- National Health and Medical Research Council [GNT1165217, GNT1140906, GNT1140851, GNT2010149]
- Australian Government Research Training Program Scholarship
- Mito Foundation
- Australian Nuclear Science and Technology Organisation (ANSTO)
- Australian Research Council [FT180100397] Funding Source: Australian Research Council
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COA7 is a crucial assembly factor for the biogenesis of mitochondrial complex IV. It interacts with SCO1 and SCO2 to catalyze copper relay and reduction of disulfide bonds, which are important for complex IV assembly.
Cytochrome c oxidase (COX) 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 loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built, progression from which requires the incorporation of copper and addition of the COX2 and COX3 modules. The crystal structure of COA7, determined to 2.4 angstrom resolution, reveals a banana-shaped molecule composed of five helix-turn-helix (alpha/alpha) repeats, tethered by disulfide bonds. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2. COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. We therefore propose that COA7 is a heme-binding disulfide reductase for regenerating the copper relay system that underpins complex IV assembly.
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