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, we reanalyzed the most extensive SARS-CoV-2-human protein-protein interactome dataset currently available. Our 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). We first present evidence demonstrating the statistical overrepresentation of actin-binding proteins among the Spike S partners/interactors. Next, we 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. We 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, we highlight that the structural domain mentioned above is a bonafide coiled-coil region. We therefore conclude that Spike S might target proteins possessing such regions. These results align well with our previous findings, which suggested that the C-terminal portion of the Spike S protein shares similarities with the human protein prominin-1/CD133. Notably, CD133 is specifically located on the apical surface of cells and is associated with microvilli, structures characterized by a dense core of cross-linked actin filaments. Collectively, our findings suggest that the interactions between SARS-CoV-2 Spike S and human proteins, potentially mediated by coiled-coil regions, may have been underestimated. This opens up new avenues of research to elucidate the mechanisms underlying SARS-CoV-2 entry and intracellular trafficking.