title: Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis.
abstract: Coenzyme Q (CoQ) is an isoprenylated quinone that is essential for cellular respiration and is synthesized in mitochondria by the combined action of at least nine proteins (COQ1-9). Although most COQ proteins are known to catalyze modifications to CoQ precursors, the biochemical role of COQ9 remains unclear. Here, we report that a disease-related COQ9 mutation leads to extensive disruption of the CoQ protein biosynthetic complex in a mouse model, and that COQ9 specifically interacts with COQ7 through a series of conserved residues. Toward understanding how COQ9 can perform these functions, we solved the crystal structure of Homo sapiens COQ9 at 2.4 Å. Unexpectedly, our structure reveals that COQ9 has structural homology to the TFR family of bacterial transcriptional regulators, but that it adopts an atypical TFR dimer orientation and is not predicted to bind DNA. Our structure also reveals a lipid-binding site, and mass spectrometry-based analyses of purified COQ9 demonstrate that it associates with multiple lipid species, including CoQ itself. The conserved COQ9 residues necessary for its interaction with COQ7 comprise a surface patch around the lipid-binding site, suggesting that COQ9 might serve to present its bound lipid to COQ7. Collectively, our data define COQ9 as the first, to our knowledge, mammalian TFR structural homolog and suggest that its lipid-binding capacity and association with COQ7 are key features for enabling CoQ biosynthesis.
authors.affiliation: Departments of Biochemistry.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Lohman
authors.affiliation: Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, NY 10027;
authors.forename: Farhad
authors.initials: F
authors.lastname: Forouhar
authors.affiliation: Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Emily T
authors.initials: ET
authors.lastname: Beebe
authors.affiliation: Departments of Biochemistry.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Stefely
authors.affiliation: Chemistry.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Minogue
authors.affiliation: Chemistry.
authors.forename: Arne
authors.initials: A
authors.lastname: Ulbrich
authors.affiliation: Departments of Biochemistry.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Stefely
authors.affiliation: Departments of Biochemistry.
authors.forename: Shravan
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain;
authors.forename: Marta
authors.initials: M
authors.lastname: Luna-Sánchez
authors.affiliation: Departments of Biochemistry.
authors.forename: Adam
authors.initials: A
authors.lastname: Jochem
authors.affiliation: Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, NY 10027;
authors.forename: Scott
authors.initials: S
authors.lastname: Lew
authors.affiliation: Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, NY 10027;
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Seetharaman
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Huang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Westphall
authors.affiliation: Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Russell L
authors.initials: RL
authors.lastname: Wrobel
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: John K
authors.initials: JK
authors.lastname: Everett
authors.affiliation: Departments of Biochemistry, Mathematics, and.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Mitchell
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain;
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.affiliation: Chemistry, Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706 Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.affiliation: Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, NY 10027; pagliarini@wisc.edu ltong@columbia.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Departments of Biochemistry, Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706; pagliarini@wisc.edu ltong@columbia.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D017434:Protein Structure, Tertiary; D014451:Ubiquinone / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D014451:Ubiquinone; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse
keywords: COQ7; COQ9; TFR family; coenzyme Q; ubiquinone