Structure and functionality of a multimeric human COQ7:COQ9 complex

Manicki, Mateusz; Aydin, Halil; Abriata, Luciano A.; Overmyer, Katherine A.; Guerra, Rachel M.; Coon, Joshua J.; Peraro, Matteo Dal; Frost, Adam; Pagliarini, David J.

doi:10.1016/j.molcel.2022.10.003

Cited by 27 publications

(24 citation statements)

References 105 publications

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“…The COQ7 polypeptide contains a loop (residues R105 to W115) that is situated between α-helix 1 and α-helix 2 and is composed predominantly of residues with hydrophobic side-chains. This loop was predicted to interact with COQ9 [ 50 ] and was recently observed at the interface between COQ7 and COQ9 in the structure determined for an octameric COQ7:COQ9 complex [ 52 ]. The residues in this loop are situated on the outer face of COQ7 ( Figure 26 A).…”

Section: Resultsmentioning

confidence: 85%

“…From gnomAD, ClinVar, Missense3D-DB, and literature we identified 60 missense SNVs of interest ( Figure 24 ; Supplemental Table S1 ). Of these variants, 47 coincided with a highly conserved region or functional residue, which were determined from the multiple sequence alignment as well as structural studies on human COQ7 [ 50 , 52 ]. Eleven of the twelve variants classified as structurally damaging by Missense3D were contained in this group ( Figure 24 ).…”

Section: Resultsmentioning

confidence: 99%

“…The human COQ7 model was obtained from the AlphaFold Protein Structure Database ( Figure 25 ) [ 39 , 54 ]. The structure of a human COQ7:COQ9 complex was recently determined (PDB: 7SSS and 7SSP) [ 52 ].…”

Section: Resultsmentioning

confidence: 99%

“…In this domain, we encounter six SNVs with relevance to this analysis. Mutations in this region have the potential to decrease COQ7-COQ9 hydrophobic, hydrogen-bonding, and salt bridge interactions noted by [ 52 ]. There are nine SNVs reported in gnomAD occurring at highly conserved or functional residues in this region ( Figure 26 B).…”

Section: Resultsmentioning

confidence: 99%

“…Functional residues in human COQ6 were determined using an S. cerevisiae Coq6 model [ 49 ]. Prior biochemical characterization, a structural model, and a recent structure of human COQ7 were used to identify the functional regions of COQ7 [ 50 , 51 , 52 ]. Prior biochemical characterization, crystal structures, and molecular dynamics simulations were used to outline the functional residues in COQ9 (PDB: 6AWL and 6DEW) [ 50 , 52 ].…”

Section: Methodsmentioning

confidence: 99%

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Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes

Wang¹,

Jain²,

Novales³

et al. 2022

Antioxidants

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Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3–COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes

Wang¹,

Jain²,

Novales³

et al. 2022

Antioxidants

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Homozygous variant in COQ7 causes autosomal recessive hereditary spastic paraplegia

Qiu,

Xiong,

Wang

et al. 2024

Ann Clin Transl Neurol

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Biallelic mutations in the coenzyme Q7 (COQ7) encoding gene were recently identified as a genetic cause of distal hereditary motor neuropathy. Here, we explored the clinical, electrophysiological, pathological, and genetic characteristics of a Chinese patient with spastic paraplegia associated with recessive variants in COQ7. This patient carried a novel c.322C>A (p.Pro108Thr) homozygous variant. Sural biopsy revealed mild mixed axonal and demyelinating degeneration. Immunoblotting showed a significant decrease in the COQ7 protein level in the patient's fibroblasts. This study confirmed that COQ7 variant as a genetic cause of HSP, and further extended spastic paraplegia to the phenotypic spectrum of COQ7‐related disorders.

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New variants expand the neurological phenotype of COQ7 deficiency

Fabra,

Paredes‐Fuentes,

Torralba Carnerero

et al. 2024

J of Inher Metab Disea

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The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3‐demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria‐associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

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Structure and functionality of a multimeric human COQ7:COQ9 complex

Cited by 27 publications

References 105 publications

Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes

Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes

Homozygous variant in COQ7 causes autosomal recessive hereditary spastic paraplegia

New variants expand the neurological phenotype of COQ7 deficiency

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