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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes
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Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes

机译：血红素合酶的低聚特性分析提供了其在真核生物中功能的见解

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摘要

Heme a is an essential cofactor for function of cytochrome c oxidase in the mitochondrial electron transport chain. Several evolutionarily conserved enzymes have been implicated in the biosynthesis of heme a, including the heme a synthase Cox15. However, the structure of Cox15 is unknown, its enzymatic mechanism and the role of active site residues remain debated, and recent discoveries suggest additional chaperone-like roles for this enzyme. Here, we investigated Cox15 in the model eukaryote Saccharomyces cerevisiae via several approaches to examine its oligomeric states and determine the effects of active site and human pathogenic mutations. Our results indicate that Cox15 exhibits homotypic interactions, forming highly stable complexes dependent upon hydrophobic interactions. This multimerization is evolutionarily conserved and independent of heme levels and heme a synthase catalytic activity. Four conserved histidine residues are demonstrated to be critical for eukaryotic heme a synthase activity and cannot be substituted with other heme-ligating amino acids. The 20-residue linker region connecting the two conserved domains of Cox15 is also important; removal of this linker impairs both Cox15 multimerization and enzymatic activity. Mutations of COX15 causing single amino acid conversions associated with fatal infantile hypertrophic cardiomyopathy and the neurological disorder Leigh syndrome result in impaired stability (S344P) or catalytic function (R217W), and the latter mutation affects oligomeric properties of the enzyme. Structural modeling of Cox15 suggests these two mutations affect protein folding and heme binding, respectively. We conclude that Cox15 multimerization is important for heme a biosynthesis and/or transfer to maturing cytochrome c oxidase.
机译：血红素a是线粒体电子传输链中细胞色素c氧化酶功能的重要辅助因子。几种在进化上保守的酶与血红素a的生物合成有关，包括血红素a合酶Cox15。然而，Cox15的结构是未知的，其酶的机制和活性位点残基的作用尚有争议，最近的发现表明该酶还具有类似伴侣的作用。在这里，我们通过几种方法研究了真核生物酿酒酵母模型中的Cox15，以检查其寡聚状态并确定活性位点和人类致病突变的作用。我们的结果表明，Cox15表现出同型相互作用，根据疏水相互作用形成高度稳定的复合物。该多聚化在进化上是保守的，并且独立于血红素水平和血红素是一种合酶催化活性。已证明四个保守的组氨酸残基对于真核血红素的合酶活性至关重要，不能被其他与血红素连接的氨基酸取代。连接Cox15的两个保守域的20个残基的连接子区域也很重要。去除该接头会损害Cox15多聚和酶活性。 COX15突变导致与致命的婴儿肥厚型心肌病和神经系统疾病Leigh综合征相关的单个氨基酸转化，导致稳定性（S344P）或催化功能（R217W）受损，而后者突变影响该酶的寡聚特性。 Cox15的结构模型表明这两个突变分别影响蛋白质折叠和血红素结合。我们得出结论，Cox15多聚化对于血红素的生物合成和/或转移至成熟的细胞色素C氧化酶很重要。

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