Interactomic Analyses and a Reverse Engineering Study Identify Specific Functional Activities of One-to-One Interactions of the S1 Subunit of the SARS-CoV-2 Spike Protein with the Human Proteome

Abstract: The S1 subunit of SARS-CoV-2 Spike has been found in the blood of covid patients and vaccinated individuals. From BioGRID, we selected 146 significant human proteins experimentally interacting with S1. Then, we derived an interactome model that facilitated the study of functional activities. Through a reverse engineering approach, we identified 27 specific one-to-one interac-tions of S1 with the human proteome. S1 interacts in this manner independently from the biological context in which it operates, be it infection or vaccination. Instead, when it works together with viral proteins, carry multiple attacks on single human proteins out, showing a different functional engagement. Through Cytoscape we showed functional implications and its tropism to human organs/tissues, such as nervous system, liver, blood, and lungs. As a single protein, S1 operates in a complex metabolic landscape which includes 2557 GO biological processes, much more than the 1430 terms controlled when operating in a group. A Data-Merging approach shows that the total proteins involved by S1 in the cell are over 60,000 with an average involvement per single bio-logical process of 26.19. However, many human proteins get entangled in over 100 biological different activities each. Clustering analysis showed statistically significant activations of many molecular mechanisms, like those related to hepatitis-B infections. This suggests potential in-volvement in carcinogenesis, based on a viral strategy that uses the ubiquitin system to impair the tumor suppressor and antiviral functions of TP53, as well as the role of RPS27A in protein turnover and cellular stress responses.