In silico evidence suggests that the SARS-CoV-2 Spike protein may target coiled-coil regions of numerous cytoskeletal and cytoskeleton-associated proteins

A bstract Understanding the interactions between host and viral envelope proteins is essential to get insights into the dynamics of viral infection. To investigate more closely the mechanisms governing SARS-CoV-2 entry and intracellular trafficking, I reanalyzed the most extensive SARS-CoV-2–human protein–protein interactome dataset currently available. My investigation centered on the Spike S protein, a key player in initiating viral infection by binding to the host cell membrane receptor Angiotensin-Converting Enzyme 2 (ACE2). I first present evidence demonstrating the statistical overrepresentation of actin-binding proteins among the Spike S partners/interactors. Next, I show that a majority of these partners contains a structural domain sharing high similarity with the C-terminal region of the Myosin II heavy chain, Myosin II being known for its roles in muscle contraction and various cellular motility processes. I subsequently demonstrate that this domain is particularly prevalent in actin-binding proteins, intermediate filaments proteins and kinesins, which all are related to the cytoskeleton known to be involved in diverse cellular functions, including endocytosis and intracellular transport — processes crucial for viral infections. Finally, I highlight that the structural domain mentioned above is a bonafide coiled-coil region. I therefore conclude that Spike S might target proteins possessing such regions. Collectively, my findings suggest that the interactions between SARS-CoV-2 Spike S and human proteins, potentially mediated by coiled-coil regions, may have been underestimated. As this work relies on in silico evidence, direct biological extrapolations require caution.