Cagliani Rachele, Forni Diego, Mozzi Alessandra, Fuchs Rotem, Hagai Tzachi, Sironi Manuela
Scientific Institute IRCCS E. MEDEA, Computational Biology Unit, Bosisio Parini 23842, Italy.
Shmunis School of Biomedicine and Cancer Research, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Comput Struct Biotechnol J. 2024 Aug 2;23:3143-3154. doi: 10.1016/j.csbj.2024.07.022. eCollection 2024 Dec.
The zinc-finger antiviral protein (ZAP) is an innate immunity sensor of non-self nucleic acids. Its antiviral activity is exerted through the physical interaction with different cofactors, including TRIM25, Riplet and KHNYN. Cellular proteins that interact with infectious agents are expected to be engaged in genetic conflicts that often result in their rapid evolution. To test this possibility and to identify the regions most strongly targeted by natural selection, we applied in silico molecular evolution tools to analyze the evolutionary history of ZAP and cofactors in four mammalian groups. We report evidence of positive selection in all genes and in most mammalian groups. On average, the intrinsically disordered regions (IDRs) embedded in the four proteins evolve significantly faster than folded domains and most positively selected sites fall within IDRs. In ZAP, the PARP domain also shows abundant signals of selection, and independent evolution in different mammalian groups suggests modulation of its ADP-ribose binding ability. Detailed analyses of the biophysical properties of IDRs revealed that chain compaction and conformational entropy are conserved across mammals. The IDRs in ZAP and KHNYN are particularly compact, indicating that they may promote phase separation (PS). In line with this hypothesis, we predicted several PS-promoting regions in ZAP and KHNYN, as well as in TRIM25. Positively selected sites are abundant in these regions, suggesting that PS may be important for the antiviral functions of these proteins and the evolutionary arms race with viruses. Our data shed light into the evolution of ZAP and cofactors and indicate that IDRs represent central elements in host-pathogen interactions.
锌指抗病毒蛋白（ZAP）是一种非自身核酸的固有免疫传感器。其抗病毒活性通过与不同辅因子（包括TRIM25、Riplet和KHNYN）的物理相互作用来发挥。与感染因子相互作用的细胞蛋白预计会参与经常导致其快速进化的遗传冲突。为了检验这种可能性并确定受自然选择影响最强烈的区域，我们应用计算机分子进化工具来分析四个哺乳动物群体中ZAP及其辅因子的进化历史。我们报告了所有基因以及大多数哺乳动物群体中存在正选择的证据。平均而言，这四种蛋白质中嵌入的内在无序区域（IDR）的进化速度明显快于折叠结构域，并且大多数正选择位点位于IDR内。在ZAP中，PARP结构域也显示出丰富的选择信号，并且在不同哺乳动物群体中的独立进化表明其ADP - 核糖结合能力受到调节。对IDR生物物理特性的详细分析表明，链压缩和构象熵在哺乳动物中是保守的。ZAP和KHNYN中的IDR特别紧凑，表明它们可能促进相分离（PS）。与此假设一致，我们在ZAP、KHNYN以及TRIM25中预测了几个促进PS的区域。这些区域中存在大量正选择位点，表明PS可能对这些蛋白质的抗病毒功能以及与病毒的进化军备竞赛很重要。我们的数据揭示了ZAP及其辅因子的进化，并表明IDR是宿主 - 病原体相互作用的核心要素。
