Role of TMDs in Class I viral fusion proteins

SUMMARYClass I fusion proteins are trimeric viral membrane proteins that mediate fusion between the virion and cellular membranes. In their prefusion state, they comprise three domains: a globular "head" domain that binds the target cell receptor, a helical "stalk" domain, and a transmembrane domain (TMD) at the carboxy-terminal end that anchors the protein in the viral membrane. However, it is now evident that the role of the TMD extends beyond simple membrane anchoring. This review explores the dynamic and regulatory functions of the TMD throughout the viral life cycle. TMDs contribute to intracellular trafficking and modulate membrane fusion activity and receptor binding. During virion assembly, they facilitate the incorporation of fusion proteins into budding particles, and influence virion formation and release. Furthermore, TMDs mediate interactions between viral and host proteins, shaping the structural organization of viral complexes, and impacting cellular responses to infection. Collectively, these findings highlight the TMD as a critical determinant of viral fitness and infectivity, underscoring its potential as a novel therapeutic target.