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Structure and functionality of a multimeric human COQ7:COQ9 complex

View ORCID ProfileMateusz Manicki, Halil Aydin, Luciano A. Abriata, Katherine A. Overmyer, Rachel M. Guerra, Joshua J. Coon, View ORCID ProfileMatteo Dal Peraro, View ORCID ProfileAdam Frost, View ORCID ProfileDavid J. Pagliarini
doi: https://doi.org/10.1101/2021.11.15.468694
Mateusz Manicki
1Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
2Morgridge Institute for Research, Madison, WI 53715, USA
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  • ORCID record for Mateusz Manicki
Halil Aydin
3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
4Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA
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Luciano A. Abriata
5Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
6Protein Production and Structure Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
7Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland
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Katherine A. Overmyer
2Morgridge Institute for Research, Madison, WI 53715, USA
8National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA
9Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI 53562, USA
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Rachel M. Guerra
1Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
2Morgridge Institute for Research, Madison, WI 53715, USA
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Joshua J. Coon
2Morgridge Institute for Research, Madison, WI 53715, USA
8National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA
9Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI 53562, USA
10Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53506, USA
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Matteo Dal Peraro
5Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
7Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland
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Adam Frost
3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
11Chan Zuckerberg Biohub, San Francisco, CA, USA
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  • For correspondence: adam.frost@ucsf.edu pagliarini@wustl.edu
David J. Pagliarini
1Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
2Morgridge Institute for Research, Madison, WI 53715, USA
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  • For correspondence: adam.frost@ucsf.edu pagliarini@wustl.edu
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Abstract

Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined ‘complex Q’ metabolon. Here we present a structure and functional analyses of a substrate- and NADH-bound oligomeric complex comprised of two complex Q subunits: the hydroxylase COQ7, which performs the penultimate step in CoQ biosynthesis, and the prenyl lipid-binding protein COQ9. We reveal that COQ7 adopts a modified ferritin-like fold with an extended hydrophobic access channel whose substrate binding capacity is enhanced by COQ9. Using molecular dynamics simulations, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for CoQ intermediates to translocate from within the bilayer to the proteins’ lipid-binding sites. Two such tetramers assemble into a soluble octamer, closed like a capsid, with lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors and coordinate subsequent synthesis steps toward producing mature CoQ.

Competing Interest Statement

Joshua J. Coon is a consultant for Thermo Scientific. Adam Frost is a shareholder and consultant for Relay Therapeutics, LLC.

Footnotes

  • ↵12 These authors contributed equally: Mateusz Manicki, Halil Aydin

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 15, 2021.
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Structure and functionality of a multimeric human COQ7:COQ9 complex
Mateusz Manicki, Halil Aydin, Luciano A. Abriata, Katherine A. Overmyer, Rachel M. Guerra, Joshua J. Coon, Matteo Dal Peraro, Adam Frost, David J. Pagliarini
bioRxiv 2021.11.15.468694; doi: https://doi.org/10.1101/2021.11.15.468694
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Structure and functionality of a multimeric human COQ7:COQ9 complex
Mateusz Manicki, Halil Aydin, Luciano A. Abriata, Katherine A. Overmyer, Rachel M. Guerra, Joshua J. Coon, Matteo Dal Peraro, Adam Frost, David J. Pagliarini
bioRxiv 2021.11.15.468694; doi: https://doi.org/10.1101/2021.11.15.468694

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