title: Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent alphavbeta3 integrin conformers.
abstract: The alphavbeta3 integrins are linked to human bleeding disorders, and pathogenic hantaviruses regulate the function of alphavbeta3 integrins and cause acute vascular diseases. alphavbeta3 integrins are present in either extended (active) or dramatically bent (inactive) structures, and interconversion of alphavbeta3 conformers dynamically regulates integrin functions. Here, we show that hantaviruses bind human alphavbeta3 integrins and that binding maps to the plexin-semaphorin-integrin (PSI) domain present at the apex of inactive, bent, alphavbeta3-integrin structures. Pathogenic hantaviruses [New York-1 virus (NY-1V) and Hantaan virus (HTNV)] bind immobilized beta3 polypeptides containing the PSI domain, and human (but not murine) beta3 polypeptides inhibit hantavirus infectivity. Substitution of human beta3 residues 1-39 for murine beta3 residues directed pathogenic hantavirus infection of nonpermissive CHO cells expressing chimeric alphavbeta3 receptors. Mutation of murine beta3 Asn-39 to Asp-39 present in human beta3 homologues (N39D) permitted hantavirus infection of cells and specified PSI domain residue interactions with pathogenic hantaviruses. In addition, cell-surface expression of alphavbeta3 locked in an inactive bent conformation conferred hantavirus infectivity of CHO cells. Our findings indicate that hantaviruses bind to a unique domain exposed on inactive integrins and, together with prior findings, suggest that this interaction restricts alphavbeta3 functions that regulate vascular permeability. Our findings suggest mechanisms for viruses to direct hemorrhagic or vascular diseases and provide a distinct target for modulating alphavbeta3-integrin functions.
authors.affiliation: Department of Medicine and Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Raymond
authors.forename: Elena
authors.initials: E
authors.lastname: Gorbunova
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gavrilovskaya
authors.forename: Erich R
authors.initials: ER
authors.lastname: Mackow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002199:Capillary Permeability; D015815:Cell Adhesion Molecules / Q000737:chemistry*; D006224:Cricetinae; D019281:Dimerization; D006476:Orthohantavirus / Q000472:pathogenicity*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D039961:Semaphorins / Q000737:chemistry*
chemical_list: D015815:Cell Adhesion Molecules; D039302:Integrin alphaVbeta3; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D039961:Semaphorins; C091529:plexin; C047981:arginyl-glycyl-aspartic acid