Membrane fusion, mediated by viral spike glycoproteins, is a key process in the infection cycle of all enveloped human and animal viruses. The overall goal of the proposed research is to understand the structural biology of viral membrane fusion. Although numerous crystal structures of the ectodomains of several enveloped virus spike glycoproteins have been determined over the years, we are only beginning to understand the structural transformations that take place when these proteins interact with membranes and how they drive membranes to fuse. In the previous grant period we have made substantial progress towards elucidating the structures of the fusion domains of influenza virus, human immunodeficiency virus, and Ebola virus in membrane environments. We have further been able to determine structural changes in these fusion domains that are conducive to membrane fusion. Most notably, membrane-bound influenza and Ebola virus fusion domains undergo large conformational changes in response to pH, i.e. there fusion trigger in the endosome. We also found that the conformation of the HIV fusion domain responds critically to cholesterol in the target membrane and that numerous critical mutants in these viral fusion domains affect their fusion function in a fashion that can be predicted by their altered structures. Based on these achievements, we now propose to test (1) the hypothesis that a deeper insertion of the Ebola virus fusion loop through a """"""""clenching of a fist"""""""" motion is responsible for Ebola GP2-mediated membrane fusion, (2) the hypothesis that cholesterol and possibly cholesterol-rich lipid domains plays a key role in human immunodeficiency and other virus entry, and (3) the hypothesis that a common membrane perturbation mechanism involving lipid order and bilayer curvature changes underlies membrane fusion promoted by influenza, HIV and Ebola viruses.

Public Health Relevance

Viral infections cause many difficult to cure diseases. One approach to combat viral infections is to find better viral entry inhibitors. This basic science project aims at a better fundamental understanding of how viruses such as influenza, HIV, and Ebola enter cells by membrane fusion. Knowledge gained from this research will help to eventually design new strategies to interrupt the infection cycle of these viruses at the stage of cell entry by membrane fusion. !

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Repik, Patricia M
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University of Virginia
Schools of Medicine
United States
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Liang, Binyong; Tamm, Lukas K (2018) Solution NMR of SNAREs, complexin and ?-synuclein in association with membrane-mimetics. Prog Nucl Magn Reson Spectrosc 105:41-53
Tamm, Lukas K (2017) Special Issue on Liposomes, Exosomes, and Virosomes. Biophys J 113:E1
Kucharska, Iga; Tamm, Lukas K (2017) Solution NMR Provides New Insight into Lipid-Protein Interaction. Biochemistry 56:4291-4292
Yang, Sung-Tae; Kreutzberger, Alex J B; Kiessling, Volker et al. (2017) HIV virions sense plasma membrane heterogeneity for cell entry. Sci Adv 3:e1700338
Lee, Jinwoo; Nyenhuis, David A; Nelson, Elizabeth A et al. (2017) Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity. Proc Natl Acad Sci U S A 114:E7987-E7996
Yang, Sung-Tae; Kreutzberger, Alex J B; Lee, Jinwoo et al. (2016) The role of cholesterol in membrane fusion. Chem Phys Lipids 199:136-143
Yang, Sung-Tae; Lim, Sung In; Kiessling, Volker et al. (2016) Site-specific fluorescent labeling to visualize membrane translocation of a myristoyl switch protein. Sci Rep 6:32866
Liang, Binyong; Tamm, Lukas K (2016) NMR as a tool to investigate the structure, dynamics and function of membrane proteins. Nat Struct Mol Biol 23:468-74
Lee, Jinwoo; Gregory, Sonia M; Nelson, Elizabeth A et al. (2016) The Roles of Histidines and Charged Residues as Potential Triggers of a Conformational Change in the Fusion Loop of Ebola Virus Glycoprotein. PLoS One 11:e0152527
Yang, Sung-Tae; Kiessling, Volker; Tamm, Lukas K (2016) Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion. Nat Commun 7:11401

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