Human COQ10A and COQ10B are distinct lipid-binding START domain proteins required for coenzyme Q function
Human COQ10A and COQ10B are distinct lipid-binding START domain proteins required for coenzyme Q function
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DOI：
10.1194/jlr.m093534
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发表时间：
2019-07-01
影响因子：
6.5
通讯作者：
Clarke, Catherine F.
中科院分区：
文献类型：
--
作者：
Tsui, Hui S.;Pham, Nguyen V. B.;Clarke, Catherine F.
辅酶Q（CoQ或泛醌）是细胞能量代谢过程中呼吸电子和质子传递的重要氧化还原活性脂质。辅酶Q也作为一种膜定位的抗氧化剂，保护细胞免受脂质过氧化作用。辅酶Q缺乏与多种人类疾病有关;辅酶Q（10）补充剂特别具有心脏保护作用。在酿酒酵母中，Coq 10是一种推定的START结构域蛋白，被认为是CoQ分子的伴侣。酵母coq 10缺失突变体（coq 10 Delta）在对数生长期不能有效地合成辅酶Q，并且是呼吸缺陷的，对氧化应激敏感。人类有两种酵母辅酶Q10的直向同源物：辅酶Q10 A和辅酶Q10 B。在这里，我们测试了人类辅助直系同源物拯救酵母突变体的能力。我们发现，无论是人类直系同源物，COQ 10A或COQ 10 B的表达，挽救酵母coq 10 Δ突变体表型，恢复功能的非发酵性碳源和敏感性的依赖性生长的氧化应激诱导的处理与PUFA。这些效应表明Coq 10在不同生物体中具有很强的功能保守性。然而，无论是辅酶Q10 A或辅酶Q10 B恢复辅酶Q生物合成时，酵母辅酶Q10 δ突变体表达。酵母Coq 10参与辅酶Q生物合成可能依赖于它与另一种蛋白质的相互作用，可能是Coq 11，这在人类中没有发现。酵母辅酶Q10和人辅酶Q10 A和辅酶Q10 B的共表达分析为这些START结构域蛋白的功能及其在其他生物途径中的潜在作用提供了额外的见解。
Coenzyme Q (CoQ or ubiquinone) serves as an essential redox-active lipid in respiratory electron and proton transport during cellular energy metabolism. CoQ also functions as a membrane-localized antioxidant protecting cells against lipid peroxidation. CoQ deficiency is associated with multiple human diseases; CoQ(10) supplementation in particular has noted cardioprotective benefits. In Saccharomyces cerevisiae, Coq10, a putative START domain protein, is believed to chaperone CoQ to sites where it functions. Yeast coq10 deletion mutants (coq10 Delta) synthesize CoQ inefficiently during log phase growth and are respiratory defective and sensitive to oxidative stress. Humans have two orthologs of yeast COQ10, COQ10A and COQ10B. Here, we tested the human co-orthologs for their ability to rescue the yeast mutant. We showed that expression of either human ortholog, COQ10A or COQ10B, rescues yeast coq10 Delta mutant phenotypes, restoring the function of respiratory-dependent growth on a nonfermentable carbon source and sensitivity to oxidative stress induced by treatment with PUFAs. These effects indicate a strong functional conservation of Coq10 across different organisms. However, neither COQ10A nor COQ10B restored CoQ biosynthesis when expressed in the yeast coq10 Delta mutant. The involvement of yeast Coq10 in CoQ biosynthesis may rely on its interactions with another protein, possibly Coq11, which is not found in humans. Coexpression analyses of yeast COQ10 and human COQ10A and COQ10B provide additional insights to functions of these START domain proteins and their potential roles in other biologic pathways.