RAPID: Identifying New ACE2 Receptor-Protein Interactions Using Evolutionary Inference

该项目的目标是确定血管紧张素转换酶2 （ACE2）与与covid-19感染相关的人类健康问题有关的其他人类蛋白质之间的潜在相互作用。ACE2是冠状病毒SARS-CoV-2结合并利用其进入和感染人类细胞的人类细胞受体。它还能调节血压，参与消化。确定先前未描述的ACE2蛋白相互作用将促进我们对其生物学功能及其对covid-19病理学的贡献的理解。更好地了解与ACE2相互作用的蛋白质可以帮助确定治疗靶点，并降低covid-19病理和并发症的严重程度，这是该项目的一个关键的更广泛的影响。该项目将使用一种新颖的计算和进化方法，基于一组与ACE2“共同进化”的哺乳动物蛋白来识别候选ACE2相互作用蛋白。这种被称为“进化速率相关”（ERC）的方法检测出在哺乳动物进化过程中显示出高度相关的进化速率的蛋白质。这些蛋白是与ACE2受体生物相互作用的强有力候选蛋白。初步结果确定了候选相互作用蛋白，这些蛋白目前还不知道是ACE2相互作用蛋白，但它们与covid-19病理相关。在前20个具有高度显著相关性的共同进化蛋白中，4个参与血液凝固级联，另外6个涉及血细胞相关表型。另外三种蛋白质与炎症过程或内毒素休克有关。这些都是令人震惊的发现，对covid-19的主要病理，包括严重血栓形成（凝血）和儿童川崎样综合征，具有明确的潜在影响。ACE2蛋白与这些血液相关蛋白之间的强烈关联此前未见报道。同时检测到对脂质代谢蛋白的强ERCs。基于这些ERCs，该项目将开发一个蛋白质相互作用网络，并将分析扩展到其他候选冠状病毒相互作用蛋白质。该RAPID奖由环境生物学部的进化过程项目提供，资金来自《冠状病毒援助、救济和经济安全法案》。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The goal of this project is to identify potential interactions between Angiotensin-converting enzyme 2 (ACE2) and other human proteins that have been implicated in human health problems related to covid-19 infection. ACE2 is the human cell receptor that the corona virus SARS-CoV-2 binds to and uses to enter and infect human cells. It also regulates blood pressure and is involved in digestion. Identifying previously undescribed ACE2 protein interactions will advance our understanding of its biological functions and its contribution to covid-19 pathology. A better understanding of the proteins with which ACE2 interacts can help identify therapeutic targets and lead to reducing the severity of covid-19 pathologies and complications, a key broader impact of this project. The project will use a novel computational and evolutionary approach to identifying candidate ACE2 interacting proteins based on a set of mammalian proteins that “coevolve” with ACE2. The approach, termed “evolutionary rate correlation” (ERC) detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are strong candidates for biological interactions with the ACE2 receptor. Preliminary results have identified candidate interacting proteins that are not currently known to be ACE2 interactors, but which are relevant to covid-19 pathologies. Among the top 20 coevolving proteins with highly significant correlations, four are involved in the blood coagulation cascade and six additional ones are implicated in blood cell related phenotypes. Three other proteins are implicated in inflammatory processes or endotoxic shock. These are striking findings, with clear potential implications to major covid-19 pathologies, including severe thrombosis (blood clotting), and Kawasaki-like syndromes in children. A strong association between ACE2 protein and these blood associated proteins has not previously been reported. Also detected are strong ERCs to lipid metabolism proteins. Based on these ERCs, the project will develop a protein interaction network, and expand the analysis to additional candidate coronavirus interacting proteins. This RAPID award is made by the Evolutionary Processes Program in the Division of Environmental Biology, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.