Molecular basis for occlusion of the jeilongvirus receptor-binding site by the elongated C-terminus

Paramyxoviral transmission between hosts may be, in part, attributed to the ability of the viral envelope-displayed receptor-binding protein (RBP) to bind to cell surface receptors of different host species. We sought to elucidate the architecture of the receptor-binding head region of the RBPs presented by jeilongviruses, a group of emerging and genetically unique paramyxoviruses belonging to the genus Jeilongvirus, family Paramyxoviridae. Structure determination of J and Beilong jeilongvirus RBPs reveals that the proteins exhibit a prototypical six-bladed β-propeller fold, present a binding site with residues associated with sialic acid recognition and hydrolysis, and bear a close structural relationship with sialic acid binding hemagglutinin-neuraminidase (HN)-type paramyxoviral RBPs. Additionally, unlike other paramyxoviruses, jeilongviruses encode an RBP with an unusually long C-terminal extension. In our dimeric Beilong virus RBP structure, we find that the C-terminal extension exchanges a hat-like domain with the central region of the β-propeller of the opposing protomer through domain-swapping. The hat-like domain occludes residues putatively associated with sialic acid binding and hydrolysis, providing a structural rationale for the absence of observed hemadsorption and neuraminidase activity. The insights gleaned from this analysis expand our appreciation of the structural palette available to the plastic paramyxoviral RBP and how their architectures may be adapted to regulate host-cell interactions at the cell surface.

The paramyxovirus receptor-binding protein (RBP) plays a primary role in determining cell and species tropism. Here, we study the RBPs of jeilongviruses, a group of paramyxoviruses that present a distinctive RBP that encodes an elongated C-terminal region. While the jeilongviral RBP structurally categorizes with paramyxoviral RBPs that interact with sialic acid during host-cell entry, the unusually long C-terminal domain was found to sterically occlude the associated binding site, suggesting that the molecule has developed strategies for autoinhibition of receptor interactions. These data expand our understanding of the architectural space occupied by paramyxoviral RBPs and the structural elaborations that may be incorporated into the paramyxovirus genome to modulate native functionality.