title: Atomic-level functional model of dengue virus Envelope protein infectivity.
abstract: A number of structures have been solved for the Envelope (E) protein from dengue virus and closely related flaviviruses, providing detailed pictures of the conformational states of the protein at different stages of infectivity. However, the key functional residues responsible for mediating the dynamic changes between these structures remain largely unknown. Using a comprehensive library of functional point mutations covering all 390 residues of the dengue virus E protein ectodomain, we identified residues that are critical for virus infectivity, but that do not affect E protein expression, folding, virion assembly, or budding. The locations and atomic interactions of these critical residues within different structures representing distinct fusogenic conformations help to explain how E protein (i) regulates fusion-loop exposure by shielding, tethering, and triggering its release; (ii) enables hinge movements between E domain interfaces during triggered structural transformations; and (iii) drives membrane fusion through late-stage zipper contacts with stem. These results provide structural targets for drug and vaccine development and integrate the findings from structural studies and isolated mutagenesis efforts into a cohesive model that explains how specific residues in this class II viral fusion protein enable virus infectivity.
authors.affiliation: Integral Molecular, Philadelphia, PA 19104.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Christian
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Kahle
authors.forename: Kimberly
authors.initials: K
authors.lastname: Mattia
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Puffer
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.forename: Adam
authors.initials: A
authors.lastname: Miller
authors.forename: Cheryl
authors.initials: C
authors.lastname: Paes
authors.forename: Edgar
authors.initials: E
authors.lastname: Davidson
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
mesh_terms: D003715:Dengue / Q000378:metabolism*; D003716:Dengue Virus / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D049410:Luciferases, Renilla; D008958:Models, Molecular; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D014759:Viral Envelope Proteins; D049410:Luciferases, Renilla