Dissecting <i>Henipavirus</i> W proteins conformational and fibrillation properties: contribution of their N‐ and C‐terminal constituent domains

The Nipah and Hendra viruses are severe human pathogens. In addition to the P protein, their P gene also encodes the V and W proteins that share with P their N-terminal intrinsically disordered domain (NTD) and possess distinct C-terminal domains (CTDs). The W protein is a key player in the evasion of the host innate immune response. We previously showed that the W proteins are intrinsically disordered and can form amyloid-like fibrils. However, structural information on W CTD (CTD_W) and its potential contribution to the fibrillation process is lacking. In this study, we demonstrate that CTD_WS are disordered and able to form dimers mediated by disulfide bridges. We also show that the NTD and the CTD_W interact with each other and that this interaction triggers both a gain of secondary structure and a chain compaction within the NTD. Finally, despite the lack of intrinsic fibrillogenic properties, we show that the CTD_W favors the formation of fibrils by the NTD both in cis and in trans. Altogether, the results herein presented shed light on the molecular mechanisms underlying Henipavirus pathogenesis and may thus contribute to the development of targeted therapies.