Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause
severe hemorrhagic fever in humans. Entry is a key step for virus infection, which starts with
binding of the envelope glycoprotein (GP) to receptors on target cells and subsequent fusion of the
virus with target cell membranes. The GP precursor is synthesized as a polypeptide, and
maturation occurs by two cleavage events, yielding a tripartite GP complex (GPC) formed by a
stable signal peptide (SSP), GP1 and GP2. The unique retained SSP interacts with GP2 and plays
essential roles in virion maturation and infectivity. GP1 is responsible for binding to the cell
receptor, and GP2 is a class I fusion protein. The native structure of the tripartite GPC is unknown.
GPC is critical for the receptor binding, membrane fusion and neutralization antibody recognition.
Elucidating the molecular mechanisms underlining the structure–function relationship of the three
subunits is the key for understanding their function and can facilitate novel avenues for combating
virus infections. This review summarizes the basic aspects and recent research of the
structure–function relationship of the three subunits. We discuss the structural basis of the
receptor-binding domain in GP1, the interaction between SSP and GP2 and its role in virion
maturation and membrane fusion, as well as the mechanism by which glycosylation stabilizes the
GPC structure and facilitates immune evasion. Understanding the molecular mechanisms involved
in these aspects will contribute to the development of novel vaccines and treatment strategies
against mammarenaviruses infection.