Coevolution Predicts Direct Interactions between mtDNA-Encoded and nDNA-Encoded Subunits of Oxidative Phosphorylation Complex I
Coevolution Predicts Direct Interactions between mtDNA-Encoded and nDNA-Encoded Subunits of Oxidative Phosphorylation Complex I
复制标题
DOI：
10.1016/j.jmb.2010.09.029
复制
发表时间：
2010-11-19
影响因子：
5.6
通讯作者：
Mishmar, Dan
中科院分区：
文献类型：
--
作者：
Gershoni, Moran;Fuchs, Angelika;Mishmar, Dan
尽管经过多年的研究，最大的哺乳动物氧化磷酸化 (OXPHOS) 复合物、NADH 泛醌氧化还原酶（复合物 I）的结构及其 45 个亚基之间的相互作用尚未完全了解。由于复合体 I 包含由线粒体 DNA (mtDNA) 和核 DNA (nDNA) 基因组编码的亚基，前者的进化速度比后者快 10 倍，因此预计并观察到紧密的细胞核协同进化。最近，我们发现了三个 nDNA 编码的复合物 I 亚基，它们经历了加速的氨基酸替换，表明它们对 mtDNA 变化率升高进行了调整。因此，它们构成了结合 mtDNA 编码亚基的绝佳候选者。在这里，我们通过分析亚基协同进化进一步解开复合物 I 内物理细胞核相互作用的网络。首先，依靠对 10 个具有已解结构的蛋白质复合物的生物信息学分析，我们表明共同进化信号以近 90% 的准确度识别了物理相互作用的亚基，从而为我们的方法提供了支持。当将此方法应用于复合物 I 内的细胞核相互作用时，我们预测复合物 I、NDUFC2 和 NDUFA1 的“速率加速”nDNA 编码亚基可能分别与 mtDNA 编码亚基 ND5/ND4 和 ND5/ND4/ND1 相互作用。此外，我们预测了 mtDNA 编码的复合物 I 亚基之间的相互作用。使用酵母双杂交系统，我们通过实验证实了预测的人类 NDUFC2 与 ND4 的相互作用，人类 NDUFA1 与 ND1 和 ND4 的相互作用，以及 NDUFC2 与 ND3 和 NDUFA1 缺乏相互作用，从而为我们的方法提供了概念证明。我们的研究首次显示了人类 OXPHOS 复合物 I 和 mtDNA 编码的亚基之间直接相互作用的证据。为破译缺乏三维结构的复合物内的亚基相互作用铺平了道路。我们的子单元交互预测方法 ComplexCorr 可在 http://webclu.bio.wzw.tum.de/complexcorr 上找到。 (C) 2010 Elsevier Ltd. 保留所有权利。
Despite years of research, the structure of the largest mammalian oxidative phosphorylation (OXPHOS) complex, NADH ubiquinone oxidoreductase (complex I), and the interactions among its 45 subunits are not fully understood. Since complex I harbors subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genomes, with the former evolving similar to 10 times faster than the latter, tight cytonuclear coevolution is expected and observed. Recently, we identified three nDNA-encoded complex I subunits that underwent accelerated amino acid replacement, suggesting their adjustment to the elevated mtDNA rate of change. Hence, they constitute excellent candidates for binding mtDNA-encoded subunits.Here, we further disentangle the network of physical cytonuclear interactions within complex I by analyzing subunits coevolution. Firstly, relying on the bioinformatic analysis of 10 protein complexes possessing solved structures, we show that signals of coevolution identified physically interacting subunits with nearly 90% accuracy, thus lending support to our approach. When applying this approach to cytonuclear interaction within complex I, we predict that the 'rate-accelerated' nDNA-encoded subunits of complex I, NDUFC2 and NDUFA1, likely interact with the mtDNA-encoded subunits ND5/ND4 and ND5/ND4/ND1, respectively. Furthermore, we predicted interactions among mtDNA-encoded complex I subunits. Using the yeast two-hybrid system, we experimentally confirmed the predicted interactions of human NDUFC2 with ND4, the interactions of human NDUFA1 with ND1 and ND4, and the lack of interaction of NDUFC2 with ND3 and NDUFA1, thus providing a proof of concept for our approach.Our study shows, for the first time, evidence for direct interactions between nDNA-encoded and mtDNA-encoded subunits of human OXPHOS complex I and paves the path towards deciphering subunit interactions within complexes lacking three-dimensional structures. Our subunit-interactions-predicting method, ComplexCorr, is available at http://webclu.bio.wzw.tum.de/complexcorr. (C) 2010 Elsevier Ltd. All rights reserved.