Masuyer Geoffrey, Taverner Alistair, MacKay Julia, Lima Marques Ana Rita, Wang Yuye, Hunter Tom, Liu Keyi, Mrsny Randall J
Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
Department of Life Sciences, University of Bath, Bath, UK.
Commun Biol. 2025 Mar 11;8(1):413. doi: 10.1038/s42003-025-07845-y.
Mono-ADP-ribosyl transferase (mART) proteins are secreted virulence factors produced by several human pathogens, the founding member being diphtheria toxin (DT). Pseudomonas aeruginosa can also secrete a mART toxin, known as exotoxin A (PE), but with an organization of its three functional domains (receptor, translocation, and enzymatic elements) that is opposite to DT. Two additional PE-like toxins (PLTs) have been identified from Vibrio cholerae and Aeromonas hydrophila, suggesting more PLT family members may exist. Database mining discovered six additional putative homologues, considerably extending this group of PLTs across a wide range of bacterial species. Here, we examine sequence and structural information for these new family members with respect to previously identified PLTs. The X-ray crystal structures of four new homologues show the conservation of critical features responsible for structure and function. This study shows the potential of these newly described toxins for the development of novel drug delivery platforms. Additionally, genomic analysis suggests horizontal gene transfer to account for the wide distribution of PLTs across a range of eubacteria species, highlighting the need to monitor emerging pathogens and their virulence factors.
单（ADP-核糖）基转移酶（mART）蛋白是几种人类病原体产生的分泌型毒力因子，其创始成员是白喉毒素（DT）。铜绿假单胞菌也能分泌一种mART毒素，即外毒素A（PE），但其三个功能结构域（受体、转位和酶元件）的组织方式与DT相反。已从霍乱弧菌和嗜水气单胞菌中鉴定出另外两种类PE毒素（PLT），这表明可能存在更多的PLT家族成员。数据库挖掘发现了另外六个假定的同源物，大大扩展了这一类PLT在广泛细菌物种中的范围。在这里，我们研究了这些新家族成员相对于先前鉴定的PLT的序列和结构信息。四个新同源物的X射线晶体结构显示了负责结构和功能的关键特征的保守性。这项研究表明了这些新描述的毒素在开发新型药物递送平台方面的潜力。此外，基因组分析表明水平基因转移是PLT在一系列真细菌物种中广泛分布的原因，这突出了监测新出现病原体及其毒力因子的必要性。
