title: Structural rearrangements of the central region of the morbillivirus attachment protein stalk domain trigger F protein refolding for membrane fusion.
abstract: It is unknown how receptor binding by the paramyxovirus attachment proteins (HN, H, or G) triggers the fusion (F) protein to fuse with the plasma membrane for cell entry. H-proteins of the morbillivirus genus consist of a stalk ectodomain supporting a cuboidal head; physiological oligomers consist of non-covalent dimer-of-dimers. We report here the successful engineering of intermolecular disulfide bonds within the central region (residues 91-115) of the morbillivirus H-stalk; a sub-domain that also encompasses the putative F-contacting section (residues 111-118). Remarkably, several intersubunit crosslinks abrogated membrane fusion, but bioactivity was restored under reducing conditions. This phenotype extended equally to H proteins derived from virulent and attenuated morbillivirus strains and was independent of the nature of the contacted receptor. Our data reveal that the morbillivirus H-stalk domain is composed of four tightly-packed subunits. Upon receptor binding, these subunits structurally rearrange, possibly inducing conformational changes within the central region of the stalk, which, in turn, promote fusion. Given that the fundamental architecture appears conserved among paramyxovirus attachment protein stalk domains, we predict that these motions may act as a universal paramyxovirus F-triggering mechanism.
authors.affiliation: Division of Experimental Clinical Research, Neurovirology Unit, DCR-VPH, Vetsuisse faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ader
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Brindley
authors.forename: Mislay
authors.initials: M
authors.lastname: Avila
authors.forename: Francesco C
authors.initials: FC
authors.lastname: Origgi
authors.forename: Johannes P M
authors.initials: JP
authors.lastname: Langedijk
authors.forename: Claes
authors.initials: C
authors.lastname: Örvell
authors.forename: Marc
authors.initials: M
authors.lastname: Vandevelde
authors.forename: Andreas
authors.initials: A
authors.lastname: Zurbriggen
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
authors.forename: Philippe
authors.initials: P
authors.lastname: Plattet
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology*; D018103:Morbillivirus / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D014760:Viral Fusion Proteins