Viral Glycoproteins, Ion Channels, and RNA-Binding Proteins

Our laboratory is investigating the molecular structure and the mechanism of replication of two enveloped RNA viruses: influenza virus and the paramyxovirus SV5. Both viruses cause diseases in humans and animals, with important biological and socioeconomic consequences.

The influenza viruses and the paramyxovirus SV5 encode seven integral membrane proteinsHA, NA, HN, F, M2, NB, and SHthat exhibit very different membrane topologies and range in size from 566 to 44 amino acids. We are particularly interested in the method of translocation of these proteins across the membrane of the endoplasmic reticulum, the role of glycosylation, and aspects of correct tertiary folding and oligomerization. These processes are a prerequisite for transport along the exocytic pathway; we are identifying cellular chaperone proteins that assist them. Analyzing the functions of these glycoproteins forms another area of interest. One project concerns the mechanism by which the F proteins cause viral-cell and cell-cell fusion. The second project entails the study of the HN glycoprotein, including its role in fusion, the signals and pathways regulating its internalization from the cell surface, and subsequent degradation. The M2 and NB proteins are critical in the replication cycle of influenza viruses. We used electrophysiological methods to demonstrate that the M2 protein has an ion-channel activity that is blocked by the antiviral drug amantadine. In collaboration with Professor Lawrence Pinto, we are performing a detailed structure-function analysis of this minimalistic ion channel. The potential ion-channel activity of NB is also under study.

Lamb, R.A. and T.S. Jardetzky. (2007). Structural basis of viral invasion: lessons from paramyxovirus F. Curr. Opin. Struct. Biol. (in press).

Chen, B.J., G.P. Leser, E. Morita and R.A. Lamb. (2007). Influenza virus hemagglutinin and neuraminidase, but not the matrix protein, are required for assembly and budding of plasmid-derived virus-like particles.  J. Virol. 81, 7111-7123.

Tompkins, S. M., Y. Lin, G.P. Leser, K.A. Kramer, D.L. Haas, E.W. Howerth, R.K. Durbin, J.E. Durbin, R. Tripp, R.A. Lamb and B. He. (2007).  Recombinant parainfluenza virus 5 (PIV5) expressing the influenza A virus hemagglutinin provides immunity in mice to influenza A virus challenge. Virology (in press).

Lamb, R.A., R.G. Paterson and T.S. Jardetzky. (2006). Paramyxovirus membrane fusion: lessons from the F and HN atomic structures. Virology 344, 30-37.

Yin, H.S., R.G. Paterson, X. Wen, R.A. Lamb, and T.S. Jardetzky. (2006). Structure of the parainfluenza virus 5 F protein in its metastable, pre-fusion conformation. Nature 439, 38-44.

Bissonnette, M.L.Z., S.A. Connolly, D.F. Young, R.E. Randall, R.G. Paterson, and R.A. Lamb. (2006). Analysis of the pH requirement for membrane fusion of different isolates of the paramyxovirus parainfluenza virus 5. J. Virol. 80, 3071-3077.

Pinto, L.H. and R.A. Lamb. (2006). The M2 protein channels of influenza A and B viruses. J. Biol. Chem. 281, 8997-9000.

Connolly, S.A. and R.A. Lamb. (2006). Paramyxovirus fusion: real-time measurement of parainfluenza virus 5 virus-cell fusion. Virology 355, 203-212.

Hale, B.G., D. Jackson, Y-H. Chen, R.A. Lamb and R.E. Randall.  (2006). Influenza A virus NS1 protein binds p85 b and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. USA 103, 14194-14199.

Lamb, R.A. and G.D. Parks. (2006). Paramyxoviridae : the viruses and their replication. Fields Virology. (Fifth Edition) (eds. D.M. Knipe and P.M. Howley), pp. 1449-1496. Lippincott, Williams and Wilkins, Philadelphia.

Lamb, R.A. (2006).  Mononegavirales. Fields Virology. (Fifth Edition) (eds. D.M. Knipe and P.M. Howley), pp. 1357-1361. Lippincott, Williams and Wilkins, Philadelphia.

Vega, R.A., D. Maspoch, C.K. Shen, J.J. Kakkassery, B.J. Chen, R.A. Lamb and C.A. Mirkin. (2006). Functional antibody arrays through metal ion-affinity templates. Chembiochem. 7, 1653-1657.

Pinto, L.H. and R.A. Lamb. (2006). Influenza virus proton channels.  Photochem. Photobiol. Sci. 5, 629-632.

Connolly, S.A., G.P. Leser, H.S. Yin, T.S. Jardetzky and R.A. Lamb. (2006). Refolding of a paramyxovirus F protein from prefusion to postfusion conformations observed by liposome binding and electron microscopy. Proc. Natl. Acad. Sci. USA. 103, 17903-17908.

Pinto, L.H. and R.A. Lamb. (2006). Controlling influenza virus replication by inhibiting its proton channel. Mol. BioSyst. 3, 18-23.

Jardetzky, T.S. and R.A. Lamb. (2004). A class act. Nature 427, 307-308.

Pinto, L.H. and R.A. Lamb. (2004). Viral ion channels as models for ion transport and targets for antiviral drug action. FEBS Lett. 560, 1-2.

Sun, M., T.A. Rothermel, L. Shuman, J.A. Aligo, S. Xu, Y. Lin, R.A. Lamb and B. He. (2004). Conserved cysteine-rich domain of paramyxovirus simian virus 5 V protein plays an important role in blocking apoptosis. J. Virol. 78, 5068-5078.

Waning, D.L., C.J. Russell, T.S. Jardetzky, and R.A. Lamb. (2004). Activation of a paramyxovirus fusion protein is modulated by inside-out signaling from the cytoplasmic tail. Proc. Natl. Acad. Sci. (USA) 101, 9217-9222.

Young, D.F., L. Andrejeva, A. Livingstone, S. Goodbourn, R.A. Lamb, P.L. Collins, R.M. Elliott and R.E. Randall. (2003). Virus replication in engineered human cells that do not respond to interferons. J. Virol. 77, 2174-2181.

Paterson, R.G., M. Takeda, Y. Ohigashi, L.H. Pinto and R. A. Lamb. (2003). Influenza B virus BM2 protein is an oligomeric integral membrane protein expressed at the cell surface. Virology 306, 7-17.

Mould, J.A., R.G. Paterson, M. Takeda, Y. Ohigashi, P. Venkataraman, R.A. Lamb and L.H. Pinto. (2003). Influenza B virus BM2 protein has ion channel activity that conducts protons across membranes. Dev. Cell 5, 175-184.

Russell, C.J., K.L. Kantor, T.S. Jardetzky and R.A. Lamb. (2003). A dual- functional paramyxovirus F protein regulatory switch segment: activation and membrane fusion. J. Cell Biol. 163, 363-374.

Takeda, M., G.P. Leser, C.J. Russell and R.A. Lamb. (2003). Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc. Natl. Acad. Sci USA 100, 14610-14617.

Tian, C., P.F. Gao, L.H. Pinto, R.A. Lamb and T.A. Cross. (2003). Initial structural and dynamic characterization of the M2 protein transmembrane and amphipathic helices in lipid bilayers. Protein Sci. 12, 2597-2605.

Takeda, M., A. Pekosz, K. Shuck, L.H. Pinto, and R.A. Lamb. (2002). Influenza A virus M2 ion channel activity is essential for efficient replication in tissue culture. J. Virol. 76, 1391-1399.

Schmitt, A.P., G.P. Leser, D.L. Waning and R.A. Lamb. (2002). Requirements for budding of paramyxovirus simian virus 5 virus-like particles. J. Virol. 76, 3952-3964.

Tang, T., F. Zaitseva, R.A. Lamb and L.H. Pinto. (2002). The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue. J. Biol. Chem. 277, 39880-39886.

Waning, D.L., A.P. Schmitt, G.P. Leser, and R.A. Lamb. (2002). Roles for the cytoplasmic tails of the fusion (F) and hemagglutinin-neuraminidase (HN) proteins in budding of the paramyxovirus simian virus 5. J. Virol. 76, 9284-9297.

He, B., R.G. Paterson, N. Stock, J.E. Durbin, R.K. Durbin, S. Goodbourn, R.E. Randall and R.A. Lamb. (2002). Recovery of paramyxovirus simian virus 5 with a V protein lacking the conserved cysteine-rich domain: The multifunctional V protein blocks both interferon-_ induction and interferon signalling. Virology 303, 15-32.

Poole, E. B. He, R.A. Lamb, R.E. Randall and S. Goodbourn. (2002). The V proteins of simian virus 5 and other paramyxoviruses inhibit induction of interferon-beta. Virology 303, 33-46.

Tian, C., K. Tobler, R.A. Lamb, L.H. Pinto, and T.A. Cross. (2002). Expression and initial structural insights from solid-state NMR of the M2 proton channel from influenza A virus. Biochemistry 41, 11294-11300.

View all publications by publications by Robert A. Lamb listed in the National Library of Medicine (PubMed).