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Review
. 2018 Mar 30;293(13):4644-4652.
doi: 10.1074/jbc.R117.816132. Epub 2017 Sep 29.

Building the CuA site of cytochrome c oxidase: A complicated, redox-dependent process driven by a surprisingly large complement of accessory proteins

Kimberly A Jett  1 , Scot C Leary  2
Affiliations
Review

"V体育平台登录" Building the CuA site of cytochrome c oxidase: A complicated, redox-dependent process driven by a surprisingly large complement of accessory proteins

Kimberly A Jett et al. J Biol Chem. .

Abstract

Cytochrome c oxidase (COX) was initially purified more than 70 years ago. A tremendous amount of insight into its structure and function has since been gleaned from biochemical, biophysical, genetic, and molecular studies. As a result, we now appreciate that COX relies on its redox-active metal centers (heme a and a3, CuA and CuB) to reduce oxygen and pump protons in a reaction essential for most eukaryotic life. Questions persist, however, about how individual structural subunits are assembled into a functional holoenzyme. Here, we focus on what is known and what remains to be learned about the accessory proteins that facilitate CuA site maturation VSports手机版. .

Keywords: COX assembly factors; CuA site formation; chaperone; copper; cytochrome c oxidase (complex IV); mitochondria; protein assembly. V体育安卓版.

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"V体育官网" Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Co-translational insertion of COX2 and export of its N terminus. A, in yeast, Pet111 binds to Cox2 mRNA to stimulate its translation. Translation is coupled with polypeptide insertion into the inner mitochondrial membrane (IMM), in a process that is facilitated by both Oxa1 and Mba1. The C terminus of Oxa1 interacts with the large ribosomal subunit, and its interaction with Mba1 positions it near the exit tunnel where Oxa1 promotes Cox2 insertion and export of its N terminus into the IMS. Cox20 interacts with Mba1 and Cox2 to stabilize and prevent degradation of the pre-protein. The N terminus of the pre-protein is then proteolytically processed to yield mature Cox2 by a peptidase complex composed of Imp1, Imp2, and Som1. B, in mammals, the hydrophilic N terminus of COX2 is much shorter than that of yeast Cox2, and it does not require proteolytic processing upon membrane insertion. Although OXA1L physically interacts with mitochondrial ribosomes and functions as an insertase, questions remain about whether it promotes co-translational insertion of COX2 into the IMM or whether this function is fulfilled by COX20. The outer mitochondrial membrane is represented by the dashed line in both panels.
Figure 2.
Figure 2.
Insertion and export of the C terminus of COX2. A, in yeast, insertion and export of the C-terminal transmembrane domain of Cox2 requires recruitment of Cox18 to the Cox2–Cox20 complex. The insertase function of Cox18 then depends on its physical association with Mss2 and Pnt1. B, in mammals, COX18 is similarly recruited to the COX2–COX20 complex where it is thought to function alone to promote insertion of the C-terminal transmembrane domain of COX2 and export of its C terminus into the IMS. The outer mitochondrial membrane is represented by the dashed line in both panels. IMM, inner mitochondrial membrane.
Figure 3.
Figure 3.
CuA site maturation of COX2. In yeast (A) and mammals (B), Cox17 and COX17, respectively, transfer Cu(I) ions to Sco1/SCO1 and Sco2/SCO2 to load the metallochaperone module. Because SCO1 and SCO2 are homodimers (30), this requires two successive rounds of COX17-dependent Cu(I) delivery to fully metallate each protein. In vitro studies support a model whereby copper-loaded SCO2 functions as a thiol-disulfide oxidoreductase to reduce the cysteinyl sulfurs of COX2 (66), in a reaction that converts Cu(I) (pink circle) to Cu(II) (purple circle) and requires COA6 function in vivo. In yeast, reduction of the cysteinyl sulfurs of Cox2 also requires Coa6 and Sco2, as well as Cox12 (69). Whether the human homolog of Cox12, COX6B, is similarly important for CuA site maturation is unclear. Upon priming of the cysteinyl sulfurs of Cox2/COX2, the CuA site is metallated by Sco1/SCO1. Whether other evolutionarily conserved COX assembly factors with poorly defined roles in COX assembly also participate in CuA site maturation remains unknown. The outer mitochondrial membrane is represented by the dashed line in both panels. 1MM, inner mitochondrial membrane.
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