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（ACE 2）与其他与新冠病毒感染相关的人类健康问题有关的人类蛋白质之间的潜在相互作用。ACE 2是冠状病毒SARS-CoV-2结合的人类细胞受体，并用于进入和感染人类细胞。它还调节血压，并参与消化。确定以前未描述的ACE 2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ACE 2与之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影响。该项目将使用一种新的计算和进化方法，根据一组与ACE 2“共同进化”的哺乳动物蛋白质来鉴定候选ACE 2相互作用蛋白。这种被称为“进化速率相关性”（ERC）的方法检测在哺乳动物进化过程中表现出高度相关进化速率的蛋白质。这些蛋白质是与ACE 2受体生物相互作用的强有力的候选者。初步结果已经确定了候选相互作用蛋白，这些蛋白目前尚不知道是ACE 2相互作用物，但与COVID-19病理相关。在具有高度显著相关性的前20种共进化蛋白质中，有4种涉及血液凝固级联反应，另外6种涉及血细胞相关表型。其他三种蛋白质与炎症过程或内毒素休克有关。这些是惊人的发现，对主要的COVID-19病理学具有明确的潜在影响，包括严重的血栓形成（凝血）和儿童川崎病样综合征。ACE 2蛋白和这些血液相关蛋白之间的强关联以前没有报道。还检测到对脂质代谢蛋白的强ERCs。基于这些ERC，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。该奖项由环境生物学部的进化过程计划颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。该奖项反映了NSF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.