Schmidt T R, Wu W, Goodman M, Grossman L I
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Mol Biol Evol. 2001 Apr;18(4):563-9. doi: 10.1093/oxfordjournals.molbev.a003836.
Mitochondrial DNA (mtDNA)-encoded proteins function in eukaryotes as subunits of respiratory complexes that also contain nuclear DNA (nDNA)-encoded subunits. The importance of functional interactions between mtDNA- and nDNA-encoded proteins was previously demonstrated by testing the survivability of cybrid cells or individuals containing nDNA and mtDNA from different populations or species. This report focuses on the multisubunit respiratory complex cytochrome c oxidase (COX), made up of both mtDNA-encoded and nDNA-encoded subunits. A combination of evolutionary and crystallographic data is employed to determine whether rates of nonsynonymous substitutions have been higher, the same, or lower for residues in close proximity that are encoded by a different genome (nDNA or mtDNA). This determination is performed by simply taking the ratio, called the interaction ratio i, of the nonsynonymous substitution rate of the close-contact residues to the nonsynonymous substitution rate of the noncontact residues. We assume that the close-contact residues (which are more likely to interact) are functionally important and that, therefore, amino acid replacements among these residues cannot escape the scrutiny of natural selection. i = 1 indicates that the close-contact residues have been under neither greater purifying selection nor greater positive selection than the noncontact residues as a specific consequence of their being encoded by separate genomes. i < 1 indicates that the close-contact residues have been under greater purifying selection but less positive selection than have the noncontact residues. Conversely, i > 1 indicates that the close-contact residues have been under less purifying but greater positive selection than have the noncontact residues. i < 1 may be referred to as a constraining interaction; i.e., the close-contact residues compared with the noncontact residues appear to be under greater structural-functional constraints. On the other hand, i > 1 may be referred to as an optimizing interaction; i.e., apparently many different amino acid replacements are required to optimize this subunit's interaction with the other subunit. A major finding is that the nDNA-encoded residues in close physical proximity to mtDNA-encoded residues evolve more slowly than the other nuclear-encoded residues (and thus display a constraining interaction), whereas the mtDNA-encoded residues in close physical proximity to nDNA-encoded residues evolve more rapidly than the other mitochondrial-encoded residues (and thus display an optimizing interaction). A possible reason for this striking difference between the nuclear- and mitochondrial-encoded COX subunits in how their functional interaction evolves is discussed.
线粒体DNA（mtDNA）编码的蛋白质在真核生物中作为呼吸复合体的亚基发挥作用，这些呼吸复合体还包含核DNA（nDNA）编码的亚基。mtDNA和nDNA编码的蛋白质之间功能相互作用的重要性先前已通过测试含有来自不同群体或物种的nDNA和mtDNA的胞质杂种细胞或个体的生存能力得以证明。本报告聚焦于由mtDNA编码和nDNA编码的亚基组成的多亚基呼吸复合体细胞色素c氧化酶（COX）。采用进化数据和晶体学数据相结合的方法，来确定由不同基因组（nDNA或mtDNA）编码的紧密相邻残基的非同义替换率是更高、相同还是更低。通过简单计算紧密接触残基的非同义替换率与非接触残基的非同义替换率之比（称为相互作用比i）来进行这一判定。我们假设紧密接触残基（更有可能发生相互作用）在功能上很重要，因此这些残基之间的氨基酸替换无法逃脱自然选择的审查。i = 1表明紧密接触残基作为由不同基因组编码的特定结果，在纯化选择或正向选择方面并不比非接触残基更强。i < 1表明紧密接触残基受到的纯化选择比非接触残基更强，但正向选择比非接触残基更少。相反，i > 1表明紧密接触残基受到的纯化选择比非接触残基更少，但正向选择比非接触残基更强。i < 1可被称为一种限制性相互作用；即与非接触残基相比，紧密接触残基似乎受到更大的结构 - 功能限制。另一方面，i > 1可被称为一种优化性相互作用；即显然需要许多不同的氨基酸替换来优化该亚基与另一个亚基的相互作用。一个主要发现是，与mtDNA编码残基紧密物理相邻的nDNA编码残基的进化速度比其他核编码残基更慢（因此表现出一种限制性相互作用），而与nDNA编码残基紧密物理相邻的mtDNA编码残基的进化速度比其他线粒体编码残基更快（因此表现出一种优化性相互作用）。文中讨论了核编码和线粒体编码的COX亚基在其功能相互作用进化方式上存在这种显著差异的一个可能原因。
