PDF(Pubmed)
Abstract：
Protein evolution is guided by structural, functional, and dynamical constraints ensuring organismal viability. Pseudogenes are genomic sequences identified in many eukaryotes that lack translational activity due to sequence degradation and thus over time have undergone \"devolution.\" Previously pseudogenized genes sometimes regain their protein-coding function, suggesting they may still encode robust folding energy landscapes despite multiple mutations. We study both the physical folding landscapes of protein sequences corresponding to human pseudogenes using the Associative Memory, Water Mediated, Structure and Energy Model, and the evolutionary energy landscapes obtained using direct coupling analysis (DCA) on their parent protein families. We found that generally mutations that have occurred in pseudogene sequences have disrupted their native global network of stabilizing residue interactions, making it harder for them to fold if they were translated. In some cases, however, energetic frustration has apparently decreased when the functional constraints were removed. We analyzed this unexpected situation for Cyclophilin A, Profilin-1, and Small Ubiquitin-like Modifier 2 Protein. Our analysis reveals that when such mutations in the pseudogene ultimately stabilize folding, at the same time, they likely alter the pseudogenes\' former biological activity, as estimated by DCA. We localize most of these stabilizing mutations generally to normally frustrated regions required for binding to other partners.
摘要：
蛋白质进化是由结构引导的，功能，和动态约束，确保组织的生存能力。假基因是在许多真核生物中鉴定的基因组序列，由于序列降解而缺乏翻译活性，因此随着时间的推移经历了“转移”。“以前的伪基因有时会恢复其蛋白质编码功能，这表明尽管有多个突变，它们仍可能编码强大的折叠能量景观。我们使用联想记忆研究了与人类假基因相对应的蛋白质序列的物理折叠景观，水调解,结构和能源模型，以及使用直接耦合分析（DCA）对其母蛋白质家族获得的进化能量景观。我们发现，通常在假基因序列中发生的突变破坏了它们稳定残基相互作用的天然全局网络，如果它们被翻译，它们就很难折叠。在某些情况下,然而,当功能约束被消除时，能量挫折感明显减少。我们分析了亲环蛋白A的这种意外情况，Profilin-1和小泛素样修饰蛋白2蛋白。我们的分析表明，当假基因中的这种突变最终稳定折叠时，同时,它们可能会改变假基因\'以前的生物活性，根据DCA的估计。我们通常将这些稳定突变中的大多数定位于与其他伴侣结合所需的正常受挫区域。
