scholarly journals Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

2015 ◽  
Vol 26 (13) ◽  
pp. 2385-2401 ◽  
Author(s):  
Manuela Bode ◽  
Michael W. Woellhaf ◽  
Maria Bohnert ◽  
Martin van der Laan ◽  
Frederik Sommer ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Specific Binding ◽  
Hydrophobic Surface ◽  
Cysteine Residue ◽  
Oxidative Modification ◽  
Intermembrane Space ◽  
Copper Binding ◽  
C Protein ◽  
Copper Transfer

Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase.

scholarly journals What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

2020 ◽  
Vol 21 (19) ◽  
pp. 6983
Author(s):  
Shadi Maghool ◽  
Michael T. Ryan ◽  
Megan J. Maher
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Molecular Mechanisms ◽  
Intermembrane Space ◽  
Copper Binding ◽  
Transport Chain ◽  
Assembly Factor ◽  
Controversial Area ◽  
Thiol Oxidoreductase ◽  
Assembly Activity

Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles in the biogenesis of these sites within COX and the failure of this intricate process, such as through mutations to these factors, disrupts COX assembly and activity. Various studies over the last ten years have revealed that the assembly factor COA6, a small intermembrane space-located protein with a twin CX9C motif, plays a role in the biogenesis of the CuA site. However, how COA6 and its copper binding properties contribute to the assembly of this site has been a controversial area of research. In this review, we summarize our current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis.

Loss of function of Sco1 and its interaction with cytochrome c oxidase

2009 ◽  
Vol 296 (5) ◽  
pp. C1218-C1226 ◽  
Author(s):  
Lukas Stiburek ◽  
Katerina Vesela ◽  
Hana Hansikova ◽  
Helena Hulkova ◽  
Jiri Zeman
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Copper Homeostasis ◽  
Copper Binding ◽  
Loss Of Function ◽  
Muscle Mitochondria ◽  
Juxtamembrane Region ◽  
Cellular Copper ◽  
The Impact ◽  
Blue Native

Sco1 and Sco2 are mitochondrial copper-binding proteins involved in the biogenesis of the CuA site in the cytochrome c oxidase (CcO) subunit Cox2 and in the maintenance of cellular copper homeostasis. Human Surf1 is a CcO assembly factor with an important but poorly characterized role in CcO biogenesis. Here, we analyzed the impact on CcO assembly and tissue copper levels of a G132S mutation in the juxtamembrane region of SCO1 metallochaperone associated with early onset hypertrophic cardiomyopathy, encephalopathy, hypotonia, and hepatopathy, assessed the total copper content of various SURF1 and SCO2-deficient tissues, and investigated the possible physical association between CcO and Sco1. The steady-state level of mutant Sco1 was severely decreased in the muscle mitochondria of the SCO1 patient, indicating compromised stability and thus loss of function of the protein. Unlike the wild-type variant, residual mutant Sco1 appeared to migrate exclusively in the monomeric form on blue native gels. Both the activity and content of CcO were reduced in the patient's muscle to ∼10–20% of control values. SCO1-deficient mitochondria showed accumulation of two Cox2 subcomplexes, suggesting that Sco1 is very likely responsible for a different posttranslational aspect of Cox2 maturation than Sco2. Intriguingly, the various SURF1-deficient samples analyzed showed a tissue-specific copper deficiency similar to that of SCO-deficient samples, suggesting a role for Surf1 in copper homeostasis regulation. Finally, both blue native immunoblot analysis and coimmunoprecipitation revealed that a fraction of Sco1 physically associates with the CcO complex in human muscle mitochondria, suggesting a possible direct relationship between CcO and the regulation of cellular copper homeostasis.

scholarly journals Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly.

2021 ◽  
Author(s):  
Luke E Formosa ◽  
Shadi Maghool ◽  
Alice J. Sharpe ◽  
Boris Reljic ◽  
Linden Muellner-Wong ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Disulfide Bonds ◽  
Initial Step ◽  
Intermembrane Space ◽  
Heme Binding ◽  
Complex Iv ◽  
Assembly Factor ◽  
Mitochondrial Intermembrane Space ◽  
Methionine Residues

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 in patients 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 at the initial step where the COX1 module is built, which requires incorporation of copper and heme cofactors. In solution, purified COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. Surprisingly, the crystal structure of COA7, determined to 2.4 angstroms resolution, reveals a banana-shaped molecule composed of five helix-turn-helix repeats, tethered by disulfide bonds, with a structure entirely distinct from proteins with characterized heme binding activities. We therefore propose a role for COA7 in heme binding/chaperoning in the mitochondrial intermembrane space, this activity being crucial for and providing a missing link in complex IV biogenesis.

scholarly journals The Interplay among Subunit Composition, Cardiolipin Content, and Aggregation State of Bovine Heart Cytochrome c Oxidase

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2588
Author(s):  
Erik Sedlák ◽  
Tibor Kožár ◽  
Andrey Musatov
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Quaternary Structure ◽  
Direct Consequence ◽  
Oxidative Modification ◽  
Subunit Composition ◽  
Current Status ◽  
Inner Mitochondrial Membrane ◽  
Aggregation State

Mitochondrial cytochrome c oxidase (CcO) is a multisubunit integral membrane complex consisting of 13 dissimilar subunits, as well as three to four tightly bound molecules of cardiolipin (CL). The monomeric unit of CcO is able to form a dimer and participate in the formation of supercomplexes in the inner mitochondrial membrane. The structural and functional integrity of the enzyme is crucially dependent on the full subunit complement and the presence of unperturbed bound CL. A direct consequence of subunit loss, CL removal, or its oxidative modification is the destabilization of the quaternary structure, loss of the activity, and the inability to dimerize. Thus, the intimate interplay between individual components of the complex is imperative for regulation of the CcO aggregation state. While it appears that the aggregation state of CcO might affect its conformational stability, the functional role of the aggregation remains unclear as both monomeric and dimeric forms of CcO seem to be fully active. Here, we review the current status of our knowledge with regard to the role of dimerization in the function and stability of CcO and factors, such as subunit composition, amphiphilic environment represented by phospholipids/detergents, and posttranslational modifications that play a role in the regulation of the CcO aggregation state.

Sign in / Sign up

Export Citation Format

Share Document