Structures of Langya virus fusion protein ectodomain in pre and post fusion conformation

Langya virus (LayV) is a paramyxovirus in theHenipavirusgenus, closely related to the deadly Nipah and Hendra viruses, that was identified in August 2022 through disease surveillance following animal exposure in eastern China. Paramyxoviruses present two glycoproteins on their surface, known as attachment and fusion proteins, that mediate entry into cells and constitute the primary antigenic targets for immune response. Here, we determine cryo-EM structures of the uncleaved LayV fusion protein (F) ectodomain in pre- and post-fusion conformations. The LayV-F protein exhibits pre- and post-fusion architectures that, despite being highly conserved across paramyxoviruses, show differences in their surface properties, in particular at the apex of the prefusion trimer, that may contribute to antigenic variability. While dramatic conformational changes were visualized between the pre- and post-fusion forms of the LayV-F protein, several domains remained invariant, held together by highly conserved disulfides. The LayV-F fusion peptide is buried within a highly conserved, hydrophobic, interprotomer pocket in the pre-fusion state and is notably less flexible than the rest of the protein, highlighting its “spring-loaded” state and suggesting that the mechanism of pre-to-post transition must involve perturbations to the pocket and release of the fusion peptide. Together, these results offer a structural basis for how the Langya virus fusion protein compares to its Henipavirus relatives and propose a mechanism for the initial step of pre- to post-fusion conversion that may apply more broadly to paramyxoviruses.ImportanceThe Henipavirus genus is quickly expanding into new animal hosts and geographic locations. This study compares the structure and antigenicity of the Langya virus fusion protein to other henipaviruses, which has important vaccine or therapeutic development implications. Furthermore, the study proposes a new mechanism to explain the early steps of the fusion initiation process that can be more broadly applied to theParamyxoviridaefamily.