title: Mutations in the N-terminal domains of nectin-1 and nectin-2 reveal differences in requirements for entry of various alphaherpesviruses and for nectin-nectin interactions.
abstract: Nectin-1 and nectin-2 are related molecules that can function with different specificities as entry receptors for mammalian alphaherpesviruses through interaction with viral glycoprotein D (gD). The normal function of members of the nectin family is to mediate cell-cell adhesion through homotypic and heterotypic nectin-nectin interactions in cadherin-based adherens junctions. We examined mutations in three equivalent regions of the N-terminal V-like domains of nectin-1 and nectin-2 to test the effects on entry of various alphaherpesviruses, nectin-nectin interactions, and interactions of the mutant nectins with gD. Mutations in region I previously shown to severely impair herpes simplex virus (HSV) entry activity, but not pseudorabies virus (PRV) or bovine herpesvirus 1 (BHV-1) entry, did not reduce homotypic trans interactions for either nectin-1 or nectin-2 or binding of nectin-3 to nectin-1. Mutations in region II, patterned after a reported single-nucleotide polymorphism in nectin-2, enhanced intracellular accumulation of both nectin-1 and nectin-2 and had a deleterious effect on all of the activities under study. Mutations in region III previously shown to reduce homotypic trans interactions of nectin-2 impaired the entry of PRV and BHV-1 when introduced into either nectin-1 or nectin-2, but only the nectin-2 mutation reduced HSV entry activity. Binding of nectin-1 to nectin-3 was not affected. Effects of the nectin-1 and nectin-2 mutations on interactions with gD did not necessarily correlate with entry activity of the mutant receptors. We can conclude that structural requirements for HSV entry, PRV and BHV-1 entry, and homotypic and heterotypic trans interactions are all different despite the previously reported ability of HSV and HSV gD to inhibit trans interactions.
authors.affiliation: Department of Microbiology-Immunology, The Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Martinez
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Spear
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism; D002450:Cell Communication; D006224:Cricetinae; D007242:Herpesvirus 1, Bovine / Q000502:physiology*; D011558:Herpesvirus 1, Suid / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D000075983:Nectins; D018139:Simplexvirus / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619014:NECTIN3 protein, human; D000075983:Nectins; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1