NMR reveals how bird flu exploits multivalency and intrinsic disorder to adapt its replication machinery to humans

Avian influenza viruses represents a recurring threat to human health. In particular highly pathogenic zoonotic avian strains, such as the currently circulating H5N1, can adapt to infect humans with high mortality, posing a catastrophic pandemic threat. Host adaptation is necessary for efficient replication and sustained human-to-human transmission. Amongst other adaptations, efficient replication in human cells requires mutations on the surface of the viral polymerase - the machine responsible for creating new copies of its genetic material.

These mutations are known to compensate differences in nature of a host protein, ANP32, that the virus somehow hijacks in the infected cell and that is required for replication. This enigmatic protein has a long disordered tail, that is 30% longer in birds than in humans. The molecular origin of the associated compensatory mechanism remained unknown until the recent study from IBS researchers and collaborators.

They used high field NMR spectroscopy to demonstrate that avian ANP32 colocalizes two viral proteins, the polymerase, and the nucleoprotein, that protects the newly produced viral genome before packaging into new viral particles. ANP32 interacts with the two viral proteins using two separate interaction sites on its disordered tail, placing them in close proximity for viral replication.

Camacho-Zarco et al noticed however that this mechanism would not be possible in human cells, because the host protein was too short to accommodate two separate interaction sites. They then demonstrated that the mutations present in the viral polymerase provide a new interaction mechanism that allows BOTH viral proteins to simultaneously bind the same stretch of human ANP32, via rapidly fluctuating, highly dynamic, multivalent interactions that colocalize the viral proteins.

This remarkable piece of molecular engineering on the part of influenza virus underlines the mechanistic plasticity of the infectious agent to overcome species barriers and achieve zoonosis, but also reveals completely new avenues for the development of potent inhibitory strategies against the ever-present pandemic threat of avian influenza.

Multivalent Dynamic Colocalization of Avian Influenza Polymerase and Nucleoprotein by Intrinsically Disordered ANP32A Reveals the Molecular Basis of Human Adaptation. Aldo R. Camacho-Zarco, Lefan Yu, Tim Krischuns, Selin Dedeoglu, Damien Maurin, Guillaume Bouvignies, Thibaut Crépin, Rob W. H. Ruigrok, Stephan Cusack, Nadia Naffakh, and Martin Blackledge. Journal of the American Chemical Society, Articles ASAP. Open Access. Publication Date (Web):September 14, 2023DOI: 10.1021/jacs.3c06965.

Contact : Martin Blackledge (IBS/Protein Dynamics and Flexibility by NMR Group)