PDF(Pubmed)
Abstract：
Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that \"coevolve\" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.
摘要：
血管紧张素转换酶2（ACE2）是冠状病毒SARS-CoV-2结合的细胞受体，用于进入和感染人类细胞。COVID-19，由冠状病毒引起的大流行疾病，涉及呼吸道疾病以外的多种病理，包括微血栓形成（微凝血），细胞因子风暴，和炎症反应影响许多器官系统。长期的慢性病可以持续数月，通常在病原体不再被检测到之后。更好地了解ACE2与之相互作用的蛋白质可以揭示与这些疾病表现相关的信息以及可能的治疗途径。我们已经采取了一种方法来预测候选ACE2相互作用蛋白，该方法使用进化推断来鉴定一组与ACE2“共同进化”的哺乳动物蛋白。的方法，称为进化速率相关性(ERC)，检测在哺乳动物进化过程中表现出高度相关进化率的蛋白质。这些蛋白质是与ACE2受体生物相互作用的候选物。该方法揭示了许多与COVID-19病理潜在相关的关键ACE2蛋白相互作用。先前已报道一些蛋白质与严重的COVID-19相关，但目前尚不清楚它们与ACE2相互作用，而其他预测的新型ACE2相互作用物与该疾病具有潜在相关性。使用蛋白质ERC的倒数排名，我们已经确定了与COVID-19病理相关的强相互关联的ACE2相关蛋白网络。ACE2与凝血途径蛋白有明确的联系，如凝血因子V和纤维蛋白原成分FGA，FGB,FGG,后者可能通过与Clusterin（清除错误折叠的细胞外蛋白）和GPR141（其功能相对未知）的ACE2连接介导。ACE2还连接到参与细胞因子信号传导和免疫反应的蛋白质（例如XCR1，IFNAR2和TLR8），以及雄激素受体(AR)。ERC预筛选方法已经阐明了相对未表征的蛋白质的可能功能和表征良好的蛋白质的可能新功能。提出了验证ERC预测的ACE2蛋白相互作用的建议。我们认为ACE2具有在SARS-CoV-2感染过程中被破坏的新型蛋白质相互作用，有助于COVID-19病理的频谱。
