title: Fusion promotion by a paramyxovirus hemagglutinin-neuraminidase protein: pH modulation of receptor avidity of binding sites I and II.
abstract: Paramyxoviruses, including the childhood respiratory pathogen human parainfluenza virus type 3 (HPIV3), possess an envelope protein hemagglutinin-neuraminidase (HN) that has receptor-cleaving (neuraminidase), as well as receptor-binding, activity. HN is a type II transmembrane glycoprotein, present on the surface of the virus as a tetramer composed of two dimers. HN is also essential for activating the fusion protein (F) to mediate merger of the viral envelope with the host cell membrane. This initial step of viral entry occurs at the host cell surface at neutral pH. The HN molecule carries out these three different critical activities at specific points in the process of viral entry, and understanding the regulation of these activities is key for the design of strategies that block infection. One bifunctional site (site I) on the HN of HPIV3 possesses both receptor binding and neuraminidase activities, and we recently obtained experimental evidence for a second receptor binding site (site II) on HPIV3 HN. Mutation of HN at specific residues at this site, which is next to the HN dimer interface, confers enhanced fusion properties, without affecting neuraminidase activity or receptor binding at neutral pH. We now demonstrate that mutations at this site II, as well as at site I, confer pH dependence on HN's receptor avidity. These mutations permit pH to modulate the binding and fusion processes of the virus, potentially providing regulation at specific stages of the viral life cycle.
authors.affiliation: Department of Pediatrics, Weill Medical College of Cornell University, 515 East 71st St., Box 309, New York, NY 10021, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Palermo
authors.forename: Matteo
authors.initials: M
authors.lastname: Porotto
authors.forename: Olga
authors.initials: O
authors.lastname: Greengard
authors.forename: Anne
authors.initials: A
authors.lastname: Moscona
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D019281:Dimerization; D015707:HN Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010224:Parainfluenza Virus 3, Human / Q000235:genetics / Q000502:physiology*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D015707:HN Protein