Abstract
Human SCO1 and SCO2 are copper-binding proteins involved in the assembly of mitochondrial cytochrome c oxidase (COX). We have determined the crystal structure of the conserved, intermembrane space core portion of apo-hSCO1 to 2.8 A. It is similar to redox active proteins, including thioredoxins (Trx) and peroxiredoxins (Prx), with putative copper-binding ligands located at the same positions as the conserved catalytic residues in Trx and Prx. SCO1 does not have disulfide isomerization or peroxidase activity, but both hSCO1 and a sco1 null in yeast show extreme sensitivity to hydrogen peroxide. Of the six missense mutations in SCO1 and SCO2 associated with fatal mitochondrial disorders, one lies in a highly conserved exposed surface away from the copper-binding region, suggesting that this region is involved in protein-protein interactions. These data suggests that SCO functions not as a COX copper chaperone, but rather as a mitochondrial redox signaling molecule.
Highlights
Human SCO1 and SCO2 are copper-binding proteins involved in the assembly of mitochondrial cytochrome c oxidase (COX)
Crystallization of the C-terminal “Core” of Human SCO1—We used limited proteolysis, N-terminal sequencing, and mass spectrometry to produce a fragment of hSCO1 suitable for MAD crystallographic analysis
The resulting core SCO1 fragment, which runs as a monomer on a size exclusion column, comprises most of the C-terminal, intermembrane space (IMS) portion of the protein (Fig. 1 and Supplementary Materials Fig. 1), and contains the CXXXC motif as well as the other residues reported to be critical for SCO function
Summary
Human SCO1 and SCO2 are copper-binding proteins involved in the assembly of mitochondrial cytochrome c oxidase (COX). Of the six missense mutations in SCO1 and SCO2 associated with fatal mitochondrial disorders, one lies in a highly conserved exposed surface away from the copper-binding region, suggesting that this region is involved in protein-protein interactions. These data suggests that SCO functions not as a COX copper chaperone, but rather as a mitochondrial redox signaling molecule. Additional nuclear gene products are required for the assembly of COX [1], including those responsible for synthesis of heme A, transport and insertion of metal cofactors, and proper co-assembly of the mitochondrial DNA- and nuclear DNA-encoded subunits. Numerous COX assembly genes have been identified in yeast [3], with many of these having human homologues, including COX10, COX11, COX15, COX17, COX19, LRPPRC, OXA1, PET112, SCO1, SCO2, and SURF1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
