Structural and functional heterogeneity of cytochrome c oxidase in S. cerevisiae

Schäfer, Jacob; Dawitz, Hannah; Ott, Martin; Ädelroth, Pia; Brzezinski, Peter

doi:10.1016/j.bbabio.2018.05.004

Cited by 13 publications

(23 citation statements)

References 34 publications

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“…Evidence is mounting for a role of Hig1 proteins in supporting CIV assembly and activity (25,26,(28)(29)(30)(41)(42)(43). It has been proposed that Hig1 type 1 proteins (specific to higher eukaryotes) are involved in the initial step of CIV assembly (42), and that Hig1 type 2 proteins (yeast Rcf1, Rcf2 and mammalian HIG2A) are involved in the later stages, for the assembly of subunits Cox13 and Cox12 in yeast.…”

Section: Discussionmentioning

confidence: 99%

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Hartley

Meunier

Pinotsis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In Saccharomyces cerevisiae, cytochrome c oxidase (CIV) forms SCs of varying stoichiometry with cytochrome bc1 (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels. Here we present the cryo-EM structures of the III2-IV1 and III2-IV2 SCs containing the hypoxic isoform Cox5B solved at 3.4 and 2.8 Å, respectively. We show that the change of isoform does not affect SC formation or activity, and that SC stoichiometry is dictated by the level of CIII/CIV biosynthesis. Comparison of the CIV5B- and CIV5A-containing SC structures highlighted few differences, found mainly in the region of Cox5. Additional density was revealed in all SCs, independent of the CIV isoform, in a pocket formed by Cox1, Cox3, Cox12, and Cox13, away from the CIII–CIV interface. In the CIV5B-containing hypoxic SCs, this could be confidently assigned to the hypoxia-induced gene 1 (Hig1) type 2 protein Rcf2. With conserved residues in mammalian Hig1 proteins and Cox3/Cox12/Cox13 orthologs, we propose that Hig1 type 2 proteins are stoichiometric subunits of CIV, at least when within a III-IV SC.

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Section: Discussionmentioning

confidence: 99%

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Hartley

Meunier

Pinotsis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…To ensure optimal respiration, the cell might be able to steer only the fully functional oxidase population into supercomplexes. However, oxidase can still accumulate in the absence of Rcf1, but a significant fraction is structurally changed (Schäfer et al, 2018b).…”

Section: Discussionmentioning

confidence: 99%

Rcf1 Modulates Cytochrome c Oxidase Activity Especially Under Energy-Demanding Conditions

et al. 2020

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The mitochondrial respiratory chain is assembled into supercomplexes. Previously, two respiratory supercomplex-associated proteins, Rcf1 and Rcf2, were identified in Saccharomyces cerevisiae, which were initially suggested to mediate supercomplex formation. Recent evidence suggests that these factors instead are involved in cytochrome c oxidase biogenesis. We demonstrate here that Rcf1 mediates proper function of cytochrome c oxidase, while binding of Rcf2 results in a decrease of cytochrome c oxidase activity. Chemical crosslink experiments demonstrate that the conserved Hig-domain as well as the fungi specific C-terminus of Rcf1 are involved in molecular interactions with the cytochrome c oxidase subunit Cox3. We propose that Rcf1 modulates cytochrome c oxidase activity by direct binding to the oxidase to trigger changes in subunit Cox1, which harbors the catalytic site. Additionally, Rcf1 interaction with cytochrome c oxidase in the supercomplexes increases under respiratory conditions. These observations indicate that Rcf1 could enable the tuning of the respiratory chain depending on metabolic needs or repair damages at the catalytic site.

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“…Contrary to initial suggestions, the presence of Rcf1 and Rcf2 is not required to achieve the III 2 -IV 1-2 supercomplex arrangement of the cytochrome bc 1 (complex III (CIII)) with the cytochrome c oxidase (complex IV (CIV)) enzyme. Rather, evidence that Rcf1 supports the assembly and activity of the CIV enzyme by physically associating with it, possibly in a dynamic way to modify the enzyme and, thereby, its stability and catalytic properties, has been presented (1,4,(11)(12)(13)(14)(15). In addition, Rcf1 has been shown to physically interact with the newly synthesized Cox3 subunit prior to Cox3's assembly into the functional CIV enzyme (1,16).…”

Section: The Yeast Mitochondrial Proteins Rcf1 and Rcf2 Are Associatementioning

confidence: 99%

“…The reason for the decreased efficiency of pumping without Cox3 is likely a structural change that raises the pKa of a key pump proton transfer group located in Cox1 near the O 2 reduction site (19,29,30). Indeed, evidence for a role of Rcf1 in supporting the structure of the heme a 3 -Cu B O 2 reduction site of CIV has been presented by Brzezinski and co-workers (12)(13)(14)(15). Cox3 plays a role in preventing the activesite alterations documented by Brzezinski and co-workers (19,31) via long-range interactions with the Cox1 subunit.…”

Section: Rcf1/rcf2 Support Maintenance Of Mitochondrial Pmf By CIVmentioning

confidence: 99%

The yeast mitochondrial proteins Rcf1 and Rcf2 support the enzymology of the cytochrome c oxidase complex and generation of the proton motive force

Strogolova

Hoang

Hosler

et al. 2019

Journal of Biological Chemistry

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Structural and functional heterogeneity of cytochrome c oxidase in S. cerevisiae

Cited by 13 publications

References 34 publications

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Rcf1 Modulates Cytochrome c Oxidase Activity Especially Under Energy-Demanding Conditions

The yeast mitochondrial proteins Rcf1 and Rcf2 support the enzymology of the cytochrome c oxidase complex and generation of the proton motive force

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