Kensche Philip R, Duarte Isabel, Huynen Martijn A
Center for Molecular and Biomolecular Informatics/Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, Nijmegen, HB, 6500, The Netherlands.
BMC Struct Biol. 2012 Aug 3;12:19. doi: 10.1186/1472-6807-12-19.
The quaternary structure of eukaryotic NADH:ubiquinone oxidoreductase (complex I), the largest complex of the oxidative phosphorylation, is still mostly unresolved. Furthermore, it is unknown where transiently bound assembly factors interact with complex I. We therefore asked whether the evolution of complex I contains information about its 3D topology and the binding positions of its assembly factors. We approached these questions by correlating the evolutionary rates of eukaryotic complex I subunits using the mirror-tree method and mapping the results into a 3D representation by multidimensional scaling.
More than 60% of the evolutionary correlation among the conserved seven subunits of the complex I matrix arm can be explained by the physical distance between the subunits. The three-dimensional evolutionary model of the eukaryotic conserved matrix arm has a striking similarity to the matrix arm quaternary structure in the bacterium Thermus thermophilus (rmsd=19 Å) and supports the previous finding that in eukaryotes the N-module is turned relative to the Q-module when compared to bacteria. By contrast, the evolutionary rates contained little information about the structure of the membrane arm. A large evolutionary model of 45 subunits and assembly factors allows to predict subunit positions and interactions (rmsd=52.6 Å). The model supports an interaction of NDUFAF3, C8orf38 and C2orf56 during the assembly of the proximal matrix arm and the membrane arm. The model further suggests a tight relationship between the assembly factor NUBPL and NDUFA2, which both have been linked to iron-sulfur cluster assembly, as well as between NDUFA12 and its paralog, the assembly factor NDUFAF2.
The physical distance between subunits of complex I is a major correlate of the rate of protein evolution in the complex I matrix arm and is sufficient to infer parts of the complex's structure with high accuracy. The resulting evolutionary model predicts the positions of a number of subunits and assembly factors.
真核生物烟酰胺腺嘌呤二核苷酸（NADH）：泛醌氧化还原酶（复合体I）是氧化磷酸化过程中最大的复合体，其四级结构大多仍未解析。此外，尚不清楚瞬时结合的组装因子与复合体I在何处相互作用。因此，我们探究复合体I的进化过程中是否包含有关其三维拓扑结构及其组装因子结合位置的信息。我们通过使用镜像树方法关联真核生物复合体I亚基的进化速率，并通过多维标度将结果映射到三维表示中，来解决这些问题。
复合体I基质臂中保守的七个亚基之间超过60%的进化相关性可以用亚基之间的物理距离来解释。真核生物保守基质臂的三维进化模型与嗜热栖热菌中的基质臂四级结构具有惊人的相似性（均方根偏差[rmsd]=19 Å），并支持先前的发现，即与细菌相比，真核生物中N模块相对于Q模块发生了转动。相比之下，进化速率几乎没有提供有关膜臂结构的信息。一个包含45个亚基和组装因子的大型进化模型能够预测亚基的位置和相互作用（rmsd=52.6 Å）。该模型支持在近端基质臂和膜臂组装过程中，NDUFAF3、C8orf38和C2orf56之间的相互作用。该模型还表明组装因子NUBPL和NDUFA2之间存在紧密关系，二者均与铁硫簇组装有关，同时也表明NDUFA12与其旁系同源物、组装因子NDUFAF2之间存在紧密关系。
复合体I亚基之间的物理距离是复合体I基质臂中蛋白质进化速率的主要相关因素，足以高精度推断复合体部分结构。由此产生的进化模型预测了许多亚基和组装因子的位置。
