TY - JOUR
T1 - Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis
AU - Lohman, Danielle C.
AU - Forouhar, Farhad
AU - Beebe, Emily T.
AU - Stefely, Matthew S.
AU - Minogue, Catherine E.
AU - Ulbrich, Arne
AU - Stefely, Jonathan A.
AU - Sukumar, Shravan
AU - Luna-Sánchez, Marta
AU - Jochem, Adam
AU - Lew, Scott
AU - Seetharaman, Jayaraman
AU - Xiao, Rong
AU - Wang, Huang
AU - Westphall, Michael S.
AU - Wrobel, Russell L.
AU - Everett, John K.
AU - Mitchell, Julie C.
AU - Ló Pez, Luis C.
AU - Coon, Joshua J.
AU - Tong, Liang
AU - Pagliarini, David J.
PY - 2014/11/4
Y1 - 2014/11/4
N2 - 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.
AB - 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.
KW - COQ7
KW - COQ9
KW - Coenzyme q
KW - Tfr family
KW - Ubiquinone
UR - http://www.scopus.com/inward/record.url?scp=84914689325&partnerID=8YFLogxK
U2 - 10.1073/pnas.1413128111
DO - 10.1073/pnas.1413128111
M3 - Article
C2 - 25339443
AN - SCOPUS:84914689325
SN - 0027-8424
VL - 111
SP - 4697
EP - 4705
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -