title: Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins.
abstract: Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes 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 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 residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common among class-1 fusion proteins, suggesting that small molecules that specifically target such motifs should prevent assembly of the trimer-of-hairpins and be of value as therapeutic inhibitors of viral entry.
authors.affiliation: The Biomedical Research Institute, College of Medicine, Ninewells Hospital, The University of Dundee, Dundee, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamb
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Schüttelkopf
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
authors.forename: David W
authors.initials: DW
authors.lastname: Brighty
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044966:Anti-Retroviral Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D002417:Cattle; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions / Q000737:chemistry / Q000378:metabolism*; D001909:Leukemia Virus, Bovine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D012190:Retroviridae / Q000378:metabolism / Q000502:physiology; D012191:Retroviridae Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D055672:Static Electricity; D013499:Surface Properties; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D044966:Anti-Retroviral Agents; D007477:Ions; D011993:Recombinant Fusion Proteins; D012191:Retroviridae Proteins; D014759:Viral Envelope Proteins