Identification of the Potential Role of the E4orf4 Protein in Adenovirus A, B, C, and D Groups in Cancer Therapy: Computational Approaches

The human adenovirus (HADV) early region 4 open reading frame 4 (E4orf4) protein plays a regulatory role in promoting viral infection by interacting with various cellular proteins. E4orf4 can induce death in cancer cells. One of the death pathways that is induced by this protein is related to the formation of membrane blebbing following the phosphorylation of tyrosine amino acids. The activation of this pathway requires the interaction of E4orf4 with Src family kinases (SFKs). The modulation mechanism of Src-dependent signaling via E4orf4 is not yet fully understood. However, evidence suggests that a physical association between the Src kinase domain and the arginine-rich motif of E4orf4 is crucial. Physically connecting E4orf4 to Src kinase leads to the deregulation of the Src-related signaling pathway, thereby inducing cytoplasmic death. In this study, we mapped the E4orf4 interaction site in Src to investigate the interaction between E4orf4 and Src in detail. We also compared the binding strength of E4orf4 proteins from different HADV groups. To this end, we performed bioinformatics structural analysis of the Src kinase domain and E4orf4 to identify E4orf4 interaction sites. The group with the lowest binding energy was predicted to be the most likely candidate for the highest cytoplasmic death in tumor cells based on the energy of the E4orf4–Src complex in various HADV groups. These results show that HADV-A and HADV-C have minimal binding energies to the E4orf4–Src complex, while the dissociation constant (Kd) of HADV-A was less than that of HADV-C. According to the obtained results, E4orf4 of the HADV-A group is more effective at triggering cytoplasmic death based on its most robust interaction with the Src kinase domain.