The Hendra and Nipah Viruses are zoonotic pathogens transmitted by bats. These viruses are associated with high mortality and morbidity rates in humans and animals. They are both members of the Henipavirus genus – a subfamily of Paramyxoviridae. They are responsible for numerous outbreaks within pigs and horses in many geographical locations including Australia and other countries within South East Asia. Lack of effective antiviral treatments against Nipah and Hendra Virus infections along with the absence of an effective vaccine for humans highlights the significant demand for the development of effective drug treatments.
Over the last decade, proteins of HeV and NiV have been studied for both their function and their structure. Since 2010, the critical role which Henipavirus W protein plays in viral infection has only intensified in its research. This protein is highly conserved in both NiV and HeV, has been found responsible for the inhibition of the type I IFN immune response due to its ability to block activation and cell signalling stages, and surprisingly has been found to localize to the host cell nucleus via an NLS. Recently, it was determined that the W protein can bind with the host 14-3-3 proteins. Family of proteins which bind to different proteins to assist in a multitude of different regulatory processes, such as signal transduction, cell cycle control and apoptotic cell death. The structure of these two proteins bound together, the reason for this binding interaction and what can this interaction mean for future research is unclear.
This study was able to provide, the first structural determination of 14-3-3 protein bound with the C-terminal domain of HeV W protein. The interaction between these two proteins was analysed structurally, revealing a phosphorylated binding determinant (Serine 449) was responsible for the interaction. In vitro functional assays confirmed that this phosphorylated Serine drove the binding interaction between 14-3-3 and W protein as well as revealing that this phosphorylation also prevents importin-α3 proteins from binding to the NLS of W protein. Theoretically preventing nuclear localisation. This study provides further insights into the dangerous Henipaviruses and potentially a platform for structure-based drug design.