The active domain of the herpes simplex virus protein ICP47: a potent inhibitor of the transporter associated with antigen processing.
The herpes simplex virus type 1 (HSV-1) protein ICP47 binds specifically to the transporter associated with antigen processing (TAP), thereby blocking peptide-binding and translocation by TAP and subsequent loading of peptides onto MHC class I molecules in the endoplasmic reticulum. In consequence, HSV-infected cells are masked for immune recognition by cytotoxic T-lymphocytes. To investigate the molecular details of this, so far, unique transporter-inhibitor interaction, the active domain and critical amino acid residues were identified by using short overlapping fragments and systematic deletions of the viral inhibitor. A fragment of 32 amino acid residues, ICP47(3-34), was found to be the minimal region harboring an activity to inhibit peptide-binding to TAP comparable to the action of the full-length protein and therefore representing the active domain. Further N or C-terminal truncations cause an abrupt loss in activity. Within the identified active domain, various mutants and chimeras of ICP47 derived from HSV-1 and HSV-2 helped to identify amino acid residues critical for TAP inhibition. On the basis of these results, therapeutic drugs could be designed that are applicable in treatment of allograft rejection or in novel vaccination strategies against HSV, restoring the ability of the immune system to recognize HSV-infected cells.
Neumann
L
L
Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, Martinsried, D-82152, Germany.
Kraas
W
W
Uebel
S
S
Jung
G
G
Tampé
R
R
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D004926:Escherichia coli; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D008285:Major Histocompatibility Complex; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D018139:Simplexvirus; D014764:Viral Proteins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000596:Amino Acids; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D011993:Recombinant Fusion Proteins; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D014764:Viral Proteins; C071692:TAP2 protein, human