Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Area of Science:

• Molecular Biology
• Virology
• Evolutionary Biology

Background:

• Angiotensin-converting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into human cells.
• COVID-19 presents diverse pathologies beyond respiratory issues, including micro-thrombosis and cytokine storms, persisting long-term.
• Understanding ACE2 interactions is crucial for elucidating COVID-19 mechanisms and developing treatments.

Purpose of the Study:

• To predict candidate proteins interacting with ACE2 using evolutionary inference.
• To identify novel ACE2 interactors relevant to COVID-19 pathologies.
• To explore potential therapeutic avenues by understanding ACE2-protein networks.

Main Methods:

• Employed evolutionary rate correlation (ERC) to detect mammalian proteins coevolving with ACE2.
• Analyzed reciprocal rankings of protein ERCs to identify interconnected protein networks.
• Focused on proteins potentially linked to COVID-19 manifestations like coagulation and immune responses.

Main Results:

• Identified key ACE2 interactions relevant to COVID-19, including previously unreported associations.
• Discovered novel ACE2 interactors potentially involved in disease pathogenesis.
• Revealed connections between ACE2 and coagulation factors (e.g., Factor V, fibrinogen), immune signaling proteins (e.g., XCR1, IFNAR2, TLR8), and Androgen Receptor (AR).

Conclusions:

• ACE2 has novel protein interactions disrupted during SARS-CoV-2 infection, contributing to COVID-19 pathologies.
• The ERC approach effectively predicts ACE2 interactors and elucidates functions of uncharacterized proteins.
• Findings provide a foundation for validating predicted interactions and developing targeted therapies for COVID-19.