Membrane fusion, mediated by viral spike glycoproteins, is a key process in the infection cycle of all enveloped human and animal viruses. The goal of this research program is to understand the structural biology of viral membrane fusion. Although the crystal structures of the ectodomains of many viral fusion proteins have been solved in recent years, the structures of the most critical protein domains that interact with the viral and host cell membranes are not known. These domains were routinely removed from the fusion proteins in order to obtain crystals that are suitable for X-ray diffraction. While the crystal structures of the ectodomains have yielded extremely valuable information about overall domain movements in these proteins, these structures do not explain how fusion proteins mediate the merging of the viral and target membranes. This task is left to the fusion and transmembrane domains. In the forthcoming grant period, we wish to determine the structures of the fusion and transmembrane domains in membranes and we wish to understand the conformational changes and mutual interactions of these domains that lead to membrane fusion. The project will concentrate on the fusion and transmembrane domains of the influenza and human immunodeficiency virus (HIV). The four specific aims are to determine: 1. structure-function relationships of the fusion domain of influenza hemagglutinin. 2. the mechanism(s) that explain(s) the coupling between the insertion of the fusion domain and fusion-promoting perturbations of the lipid bilayer. 3. the structural role of the transmembrane domain in membrane fusion. 4. the membrane structure of the fusion domain of HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI030557-15
Application #
7032249
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Lacourciere, Karen A
Project Start
1991-09-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
15
Fiscal Year
2006
Total Cost
$324,445
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
Lai, Alex L; Moorthy, Anna Eswara; Li, Yinling et al. (2012) Fusion activity of HIV gp41 fusion domain is related to its secondary structure and depth of membrane insertion in a cholesterol-dependent fashion. J Mol Biol 418:3-15
Smith, Everett Clinton; Gregory, Sonia M; Tamm, Lukas K et al. (2012) Role of sequence and structure of the Hendra fusion protein fusion peptide in membrane fusion. J Biol Chem 287:30035-48
Wan, Chen; Kiessling, Volker; Cafiso, David S et al. (2011) Partitioning of synaptotagmin I C2 domains between liquid-ordered and liquid-disordered inner leaflet lipid phases. Biochemistry 50:2478-85
Arouri, Ahmad; Kiessling, Volker; Tamm, Lukas et al. (2011) Morphological changes induced by the action of antimicrobial peptides on supported lipid bilayers. J Phys Chem B 115:158-67
Lai, Alex L; Tamm, Lukas K (2010) Shallow boomerang-shaped influenza hemagglutinin G13A mutant structure promotes leaky membrane fusion. J Biol Chem 285:37467-75
Tamm, Lukas K; Groves, Jay T (2009) Supported membranes in structural biology. J Struct Biol 168:1-2
Murray, David H; Tamm, Lukas K; Kiessling, Volker (2009) Supported double membranes. J Struct Biol 168:183-9
Kiessling, Volker; Wan, Chen; Tamm, Lukas K (2009) Domain coupling in asymmetric lipid bilayers. Biochim Biophys Acta 1788:64-71
Lai, Alex L; Tamm, Lukas K (2007) Locking the kink in the influenza hemagglutinin fusion domain structure. J Biol Chem 282:23946-56

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