The long-term goals of this project are to provide a structural foundation for understanding the process of pramyxovirus infection, including the specificity of cell recognition and initiation of paramyxovirus infection, including the specificity of cell recognition and initiation of membrane fusion events. The proposed studies are focused on elucidating the relationship of F protein structural states to potential mechanisms of membrane fusion. Studies of the influence virus HA have contributed greatly to our understanding of the analogous recognition and membrane fusion mechanisms of orthomyxoviruses. However, the crystal structure of the SV5 F1 core in particular has shown that new insights can be gained from the study of other viral fusion proteins. Many outstanding questions remain to be clarified in paramyxovirus mediated entry into cells, including the molecular basis for its initiation, the role of potential """"""""metastable"""""""" conformational states in the F proteins, and the energetics of bilayer fusion. In collaboration with the Lamb Laboratory at Northwestern, we will be able to take both a structural and functional approach to understanding these processes. The results of these studies will provide novel information on protein-mediated membrane fusion events that will have significant implications in the development of new anti-viral medications. The observation of structural similarities in viral and cellular protein complexes involved in membrane fusion further suggests that studies of the paramyxovirus F proteins will contribute to our fundamental understanding of a process common to all cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Experimental Virology Study Section (EVR)
Program Officer
Chin, Jean
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Wen, Xiaolin; Mousa, Jarrod J; Bates, John T et al. (2017) Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus. Nat Microbiol 2:16272
Wong, Joyce J W; Paterson, Reay G; Lamb, Robert A et al. (2016) Structure and stabilization of the Hendra virus F glycoprotein in its prefusion form. Proc Natl Acad Sci U S A 113:1056-61
Song, Albert S; Poor, Taylor A; Abriata, Luciano A et al. (2016) Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins. Proc Natl Acad Sci U S A 113:E3844-51
Adu-Gyamfi, Emmanuel; Kim, Lori S; Jardetzky, Theodore S et al. (2016) Mutagenesis of Paramyxovirus Hemagglutinin-Neuraminidase Membrane-Proximal Stalk Region Influences Stability, Receptor Binding, and Neuraminidase Activity. J Virol 90:7778-88
Adu-Gyamfi, Emmanuel; Kim, Lori S; Jardetzky, Theodore S et al. (2016) Flexibility of the Head-Stalk Linker Domain of Paramyxovirus HN Glycoprotein Is Essential for Triggering Virus Fusion. J Virol 90:9172-81
Poor, Taylor A; Song, Albert S; Welch, Brett D et al. (2015) On the stability of parainfluenza virus 5 F proteins. J Virol 89:3438-41
Bose, Sayantan; Jardetzky, Theodore S; Lamb, Robert A (2015) Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry. Virology 479-480:518-31
Jardetzky, Theodore S; Lamb, Robert A (2014) Activation of paramyxovirus membrane fusion and virus entry. Curr Opin Virol 5:24-33
Welch, Brett D; Paduch, Marcin; Leser, George P et al. (2014) Probing the functions of the paramyxovirus glycoproteins F and HN with a panel of synthetic antibodies. J Virol 88:11713-25
Bose, Sayantan; Song, Albert S; Jardetzky, Theodore S et al. (2014) Fusion activation through attachment protein stalk domains indicates a conserved core mechanism of paramyxovirus entry into cells. J Virol 88:3925-41

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