Becker, J. E. | Search bioRxiv

bioRxiv2024

Structure of a zoonotic H5N1 hemagglutinin reveals a receptor-binding site occupied by an auto-glycan

Highly pathogenic avian influenza has spilled into many mammals, most notably U.S. dairy cows with several dozen human breakthrough infections. Zoonotic crossovers, with hemagglutinins mutated to enhance viral ability to use human 2-6-linked sialic acid receptors versus avian 2-3-linked ones, highlight the pandemic risk. To gain insight into these crossovers, we determined the cryo-EM structure of hemagglutinin from the zoonotic H5N1 A/Texas/37/2024 strain (clade 2.3.4.4b) in complex with a previously reported neutralizing antibody. Surprisingly, we found that the receptor-binding site of this H5N1 hemagglutinin was already occupied by an 2-3-linked sialic acid and that this glycan emanated from asparagine N169 of a neighboring protomer on hemagglutinin itself. This structure thus highlights recognition by influenza hemagglutinin of an "auto"-2-3-linked sialic acid from N169, an N-linked glycan conserved in 95% of H5 strains, and adds "auto-glycan recognition" to the complexities surrounding H5N1 zoonosis. HighlightsO_LIWe report the structure of hemagglutinin from the zoonotic H5N1 strain A/Texas/37/2024 from clade 2.3.4.4b responsible for the current H5N1 outbreak C_LIO_LIStructural analysis revealed that each receptor-binding site of H5N1 A/Texas/37/2024 HA is bound to an "auto" sialic acid originating from glycan N169 on an adjacent protomer C_LIO_LIThis structure provides new aspects of receptor binding for a highly pathogenic strain of avian influenza, and raises questions about the impact of auto-binding sialic acid, especially with respect to zoonosis C_LI

immunology↗

bioRxiv2024

Cis inhibition of co-expressed DIPs and Dprs shapes neural development

In Drosophila, two interacting adhesion protein families, Dprs and DIPs, coordinate the assembly of neural networks. While intercellular DIP/Dpr interactions have been well characterized, DIPs and Dprs are often co-expressed within the same cells, raising the question as to whether they also interact in cis. We show, in cultured cells and in vivo, that DIP- and DIP-{delta} can interact in cis with their ligands, Dpr6/10 and Dpr12, respectively. When co-expressed in cis with their cognate partners, these Dprs regulate the extent of trans binding, presumably through competitive cis interactions. We demonstrate the neurodevelopmental effects of cis inhibition in fly motor neurons and in the mushroom body. We further show that a long disordered region of DIP- at the C-terminus is required for cis but not trans interactions, likely because it alleviates geometric constraints on cis binding. Thus, the balance between cis and trans interactions plays a role in controlling neural development.

biochemistry↗