Viral Membrane Fusion

Membrane Fusion in Viral Infection

Our laboratory is interested in unraveling the mechanisms of membrane fusion when enveloped viruses such as influenza, HIV, and Ebola enter their respective host cells. To do so, we take combined structural, biophysical, and cell biological approaches. Ultimately we want to understand how triggered fusion proteins deform their own and the host cells’ membranes so that they merge into a single membrane and thereby deliver the viral genome into the cell. Understanding the fundamental biological underpinnings of this process should also facilitate the discovery of new antiviral therapies.

Although the structures of the soluble domains of many viral fusion proteins have been solved, the mechanism of membrane fusion is still poorly understood. We are studying the structures and interactions of viral fusion proteins in lipid bilayers. We have worked out a detailed 'spring-loaded boomerang' model of how influenza HA interacts with viral and cellular membranes. We have determined the structures of the influenza HA fusion domain in lipid bilayers by NMR and spin-label EPR spectroscopy at resting and fusion pH and, by studying many mutants, we have established numerous structure-function relationships in this process (see here for pictures). More recently we have also engaged in similar studies with the fusion domain of HIV gp41 and, in collaboration with Judith White’s laboratory, with the fusion domain of Ebola virus GP2.

Tamm, L.K., Lai, A.L., Li Y..(2007) Combined NMR and EPR spectroscopy to determine structures of viral fusion domains in membranes. Bioch. Biop. Acta . 1768: 3052-3060 (Full text in PDF)

Lai, A.L. and Tamm, L.K. (2007) Locking the kink in the influenza hemagglutinin fusion domain structure. J. Biol. Chem. 282:23946-23956. (Full text in PDF) (Supplement)

Li, Y. and Tamm, L.K. (2007) Structure and plasticity of the human immunodeficiency virus gp41 fusion domain in lipid micelles and bilayers. Biophys. J. 93:876-885. (Full text in PDF) (Supplement)

Lai AL, Park H, White JM, Tamm LK. (2006). Fusion Peptide of influenza hemagglutinin requires a fixed angle boomerang structure for activity. J Biol Chem. 2006 Mar 3;281(9):5760-70 (Full text in PDF)

Li, Y., Han,X., Lai, A. LQ, Bushweller J.H., Cafiso D.S., Tamm L.K. (2005). Membrane Structures of the Hemifusion-Inducing Fusion Peptide Mutant G1S and the Fusion Blocking Mutant G1V of Influenza Virus Hemagglutinin Suggest a mechanism for Pore Opening in Membrane Fusion. Journal of Virology Vol.79 No.18: 12065-12076. (Full text in PDF)

Tamm, L.K., F. Abildgaard, A. Arora, H. Blad, and J.H. Bushweller (2003). Structure, dynamics and function of the outer membrane protein A (OmpA) and influenza hemagglutinin fusion domain in detergent micelles by solution NMR. (Minireview) FEBS Lett. 555: 139-143. (Full text in PDF)

Tamm, L.K., J. Crane, and V. Kiessling (2003). Membrane fusion: a structural perspective on the interplay of lipids and proteins. (Review) Curr. Op. Struct. Biol. 13: 453-466. (Full text in PDF)

Tamm, L.K. (2003). Hypothesis: spring-loaded boomerang mechanism of influenza hemagglutinin-mediated membrane fusion. (Review) Biochim. Biophys. Acta. 1614: 14-23. (Full text in PDF)

Li, Y., X. Han, and L.K. Tamm (2003). Thermodynamics of Fusion Peptide-Membrane Interactions. Biochemistry. 42: 7245-7251. (Full text in PDF)

Tamm, L.K., X. Han, Y. Li, and A.L. Lai (2002). Structure and function of membrane fusion peptides. (Review) Biopolymers (Peptide Science). 66: 249-260. (Full text in PDF)

Tamm, L.K. (2002). Peptide Interactions in Supported Monolayers and Bilayers. (Review) Current Topics in Membranes. 52: 191-202.

Han, X., J.H. Bushweller, D.S. Cafiso, and L.K. Tamm (2001). Membrane structure and fusion triggering conformational change of the fusion domain from influenza hemagglutinin. Nature Struct. Biol. 8: 715-720. (Full text in PDF)

Tamm, L.K. and X. Han (2000). Viral fusion peptides: A tool set to disrupt and connect biological membranes. (Review) Bioscience Reports. 20: 501-518.

Han, X. and L.K. Tamm (2000). A host-guest system to study structure-function relationships of membrane fusion peptides. Proc. Natl. Acad. Sci. U.S.A. 97: 13097-13102.(Full text in PDF)

Han, X. and L.K. Tamm (2000). pH-dependent self-association of influenza hemagglutinin fusion peptides in lipid bilayers. J. Mol. Biol. 304: 953-965. (Full text in PDF)

Tatulian, S.A. and L.K. Tamm (2000). Secondary structure, orientation, oligomerization, and lipid interactions of the transmembrane domain of influenza hemagglutinin. Biochemistry. 39: 496-507. (Full text in PDF)

Gray, C. and L.K. Tamm (1998). pH-induced conformational changes of membrane-bound influenza hemagglutinin and its effect on target lipid bilayers. Protein Sci. 7: 2359-2373. (Full text in HTML)

Gray, C. and L.K. Tamm (1997). Structural studies on membrane-embedded influenza hemagglutinin and its fragments. Protein Sci. 6: 1993-2006. (Full text in HTML)

Tatulian, S.A., P. Hinterdorfer, G. Baber, and L.K. Tamm (1995). Influenza hemagglutinin assumes a tilted conformation during membrane fusion. EMBO J. 14: 5514-5523.

Hinterdorfer, P., G. Baber, and L.K. Tamm (1994). Reconstitution of membrane fusion sites. A total internal reflection fluorescence microscopy study of influenza hemagglutinin-mediated membrane fusion. J. Biol. Chem. 269: 20360-20368.