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Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms.

ABSTRACT: Paramyxoviruses-including important pathogens like parainfluenza, measles, and Nipah viruses-use a receptor binding protein [hemagglutinin-neuraminidase (HN) for parainfluenza] and a fusion protein (F), acting in a complex, to enter cells. We use cryo-electron tomography to visualize the fusion complex of human parainfluenza virus 3 (HN/F) on the surface of authentic clinical viruses at a subnanometer resolution sufficient to answer mechanistic questions. An HN loop inserts in a pocket on F, showing how the fusion complex remains in a ready but quiescent state until activation. The globular HN heads are rotated with respect to each other: one downward to contact F, and the other upward to grapple cellular receptors, demonstrating how HN/F performs distinct steps before F activation. This depiction of viral fusion illuminates potentially druggable targets for paramyxoviruses and sheds light on fusion processes that underpin wide-ranging biological processes but have not been visualized in situ or at the present resolution.

SUBMITTER: Marcink TC

PROVIDER: S-EPMC9917000 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms.

Marcink Tara C TC Zipursky Gillian G Cheng Wenjing W Stearns Kyle K Stenglein Shari S Golub Kate K Cohen Frances F Bovier Francesca F Pfalmer Daniel D Greninger Alexander L AL Porotto Matteo M des Georges Amedee A Moscona Anne A

Science advances 20230210 6

Paramyxoviruses-including important pathogens like parainfluenza, measles, and Nipah viruses-use a receptor binding protein [hemagglutinin-neuraminidase (HN) for parainfluenza] and a fusion protein (F), acting in a complex, to enter cells. We use cryo-electron tomography to visualize the fusion complex of human parainfluenza virus 3 (HN/F) on the surface of authentic clinical viruses at a subnanometer resolution sufficient to answer mechanistic questions. An HN loop inserts in a pocket on F, sho ...[more]

PMID: 36763666

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Project description:Ebolavirus (EBOV) and Marburgvirus (MARV) that compose the filovirus family of negative strand RNA viruses infect a broad range of mammalian cells. Recent studies indicate that cellular entry of this family of viruses requires a series of cellular protein interactions and molecular mechanisms, some of which are unique to filoviruses and others are commonly used by all viral glycoproteins. Details of this entry pathway are highlighted here. Virus entry into cells is initiated by the interaction of the viral glycoprotein(1) subunit (GP(1)) with both adherence factors and one or more receptors on the surface of host cells. On epithelial cells, we recently demonstrated that TIM-1 serves as a receptor for this family of viruses, but the cell surface receptors in other cell types remain unidentified. Upon receptor binding, the virus is internalized into endosomes primarily via macropinocytosis, but perhaps by other mechanisms as well. Within the acidified endosome, the heavily glycosylated GP(1) is cleaved to a smaller form by the low pH-dependent cellular proteases Cathepsin L and B, exposing residues in the receptor binding site (RBS). Details of the molecular events following cathepsin-dependent trimming of GP(1) are currently incomplete; however, the processed GP(1) specifically interacts with endosomal/lysosomal membranes that contain the Niemann Pick C1 (NPC1) protein and expression of NPC1 is required for productive infection, suggesting that GP/NPC1 interactions may be an important late step in the entry process. Additional events such as further GP(1) processing and/or reducing events may also be required to generate a fusion-ready form of the glycoprotein. Once this has been achieved, sequences in the filovirus GP(2) subunit mediate viral/cellular membrane fusion via mechanisms similar to those previously described for other enveloped viruses. This multi-step entry pathway highlights the complex and highly orchestrated path of internalization and fusion that appears unique for filoviruses.

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Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms.

Publications

Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms.

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