Comparative structural analysis of retroviral fusion proteins identifies regions that modulate...
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MEETING ABSTRACT Open Access Comparative structural analysis of retroviral fusion proteins identifies regions that modulate membrane fusion: a potential retroviral achilles heal? Daniel Lamb 1 , Alexander W Schüttelkopf 2 , Daan M F van Aalten 2 , David W Brighty 1* From 15th International Conference on Human Retroviruses: HTLV and Related Viruses Leuven and Gembloux, Belgium. 5-8 June 2011 Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure pro- motes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer of hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that through electrostatic interactions with of a chloride ion the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic resi- dues that cluster around this pocket are critical to mem- brane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and elec- trostatic interactions with small ions are common leit- motifs among class-1 fusion proteins. We will discuss the impact of these observations in light of current models of membrane fusion and as potential targets for therapeutic inhibition of viral entry. Author details 1 The Biomedical Research Institute, College of Medicine, Ninewells Hospital, University, Dundee, Scotland, DD1 9SY, UK. 2 Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, DD1 5EH2, UK. Published: 6 June 2011 doi:10.1186/1742-4690-8-S1-A163 Cite this article as: Lamb et al.: Comparative structural analysis of retroviral fusion proteins identifies regions that modulate membrane fusion: a potential retroviral achilles heal? Retrovirology 2011 8(Suppl 1): A163. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit * Correspondence: [email protected] 1 The Biomedical Research Institute, College of Medicine, Ninewells Hospital, University, Dundee, Scotland, DD1 9SY, UK Full list of author information is available at the end of the article Lamb et al. Retrovirology 2011, 8(Suppl 1):A163 http://www.retrovirology.com/content/8/S1/A163 © 2011 Lamb et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Transcript of Comparative structural analysis of retroviral fusion proteins identifies regions that modulate...
MEETING ABSTRACT Open Access
Comparative structural analysis of retroviralfusion proteins identifies regions that modulatemembrane fusion: a potential retroviral achillesheal?Daniel Lamb1, Alexander W Schüttelkopf2, Daan M F van Aalten2, David W Brighty1*
From 15th International Conference on Human Retroviruses: HTLV and Related VirusesLeuven and Gembloux, Belgium. 5-8 June 2011
Refolding of viral class-1 membrane fusion proteinsfrom a native state to a trimer-of-hairpins structure pro-motes entry of viruses into cells. Here we present thestructure of the bovine leukaemia virus transmembraneglycoprotein (TM) and identify a group of asparagineresidues at the membrane-distal end of the trimer ofhairpins that is strikingly conserved among divergentviruses. These asparagines are not essential for surfacedisplay of pre-fusogenic envelope. Instead, substitutionof these residues dramatically disrupts membrane fusion.Our data indicate that through electrostatic interactionswith of a chloride ion the asparagine residues promoteassembly and profoundly stabilize the fusion-activestructures that are required for viral envelope-mediatedmembrane fusion. Moreover, the BLV TM structurealso reveals a charge-surrounded hydrophobic pocket onthe central coiled coil and interactions with basic resi-dues that cluster around this pocket are critical to mem-brane fusion and form a target for peptide inhibitors ofenvelope function. Charge-surrounded pockets and elec-trostatic interactions with small ions are common leit-motifs among class-1 fusion proteins. We will discussthe impact of these observations in light of currentmodels of membrane fusion and as potential targets fortherapeutic inhibition of viral entry.
Author details1The Biomedical Research Institute, College of Medicine, Ninewells Hospital,University, Dundee, Scotland, DD1 9SY, UK. 2Division of Molecular
Microbiology, College of Life Sciences, University of Dundee, Dundee, DD15EH2, UK.
Published: 6 June 2011
doi:10.1186/1742-4690-8-S1-A163Cite this article as: Lamb et al.: Comparative structural analysis ofretroviral fusion proteins identifies regions that modulate membranefusion: a potential retroviral achilles heal? Retrovirology 2011 8(Suppl 1):A163.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submit
* Correspondence: [email protected] Biomedical Research Institute, College of Medicine, Ninewells Hospital,University, Dundee, Scotland, DD1 9SY, UKFull list of author information is available at the end of the article
Lamb et al. Retrovirology 2011, 8(Suppl 1):A163http://www.retrovirology.com/content/8/S1/A163
© 2011 Lamb et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
