PDF(Pubmed)
Abstract：
Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps link the early proteins with late proteins. The FtsQBL complex is highly conserved as a component across bacteria. Pathogens like Vibrio cholerae, Mycobacterium ulcerans, Mycobacterium leprae, and Chlamydia trachomatis are the causative agents of the bacterial Neglected Tropical Diseases Cholera, Buruli ulcer, Leprosy, and Trachoma, respectively, some of which seemingly lack known homologs for some of the FtsQBL complex proteins. In the absence of experimental characterization, either due to insufficient resources or the massive increase in novel sequences generated from genomics, functional annotation is traditionally inferred by sequence similarity to a known homolog. With the advent of accurate protein structure prediction methods, features both at the fold level and at the protein interaction level can be used to identify orthologs that cannot be unambiguously identified using sequence similarity methods. Using the FtsQBL complex proteins as a case study, we report potential remote homologs using Profile Hidden Markov models and structures predicted using AlphaFold. Predicted ortholog structures show conformational similarity with corresponding E. coli proteins irrespective of their level of sequence similarity. Alphafold multimer was used to characterize remote homologs as FtsB or FtsL, when they were not sufficiently distinguishable at both the sequence or structure level, as their interactions with FtsQ and FtsW play a crucial role in their function. The structures were then analyzed to identify functionally critical regions of the proteins consistent with their homologs and delineate regions potentially useful for inhibitor discovery.
摘要：
细胞分裂是细菌细胞分裂的重要过程,它涉及超过25种必需/非必需细胞分裂蛋白，这些蛋白形成称为分裂体的蛋白质复合物。分裂体的核心是蛋白质FtsB和FtsL与FtsQ结合形成复杂的FtsQBL，这有助于将早期蛋白质与晚期蛋白质联系起来。FtsQBL复合物作为跨细菌的组分是高度保守的。像霍乱弧菌这样的病原体,溃疡分枝杆菌,麻风分枝杆菌,沙眼衣原体是细菌性被忽视的热带病霍乱的病原体，布鲁里溃疡,麻风病,和沙眼,分别,其中一些似乎缺乏一些FtsQBL复杂蛋白的已知同源物。在没有实验表征的情况下，由于资源不足或基因组学产生的新序列大量增加，传统上，功能注释是通过与已知同源物的序列相似性来推断的。随着准确的蛋白质结构预测方法的出现，折叠水平和蛋白质相互作用水平的特征均可用于鉴定使用序列相似性方法无法明确鉴定的直向同源物。使用FtsQBL复合蛋白作为案例研究，我们使用ProfileHiddenMarkov模型和使用AlphaFold预测的结构报告潜在的远程同源物。预测的直向同源结构显示与相应的大肠杆菌蛋白的构象相似性,而与它们的序列相似性水平无关。Alphafold多聚体用于将远程同源物表征为FtsB或FtsL，当它们在序列或结构水平上都无法充分区分时，因为它们与FtsQ和FtsW的相互作用在它们的功能中起着至关重要的作用。然后分析结构以鉴定与其同源物一致的蛋白质的功能关键区域,并描绘可能用于抑制剂发现的区域。
