Determination of the structural basis for selective binding of Epstein-Barr virus to human complement receptor type 2.
Epstein-Barr virus (EBV) is an oncogenic herpesvirus that selectively infects and immortalizes human B lymphocytes. One determinant of this narrow tropism is human CR2, the only viral receptor within the superfamily of proteins that contain short consensus repeats (SCRs). Human CR2 serves as a receptor for both C3dg and the gp350/220 glycoprotein of EBV, and binds the monoclonal antibody (mAb) OKB7, which blocks binding of both ligands to the receptor. In contrast, although murine CR2 is capable of binding human C3dg and this interaction can be blocked with the mAb 7G6, it does not bind OKB7 or EBV. We have determined the structural basis for absolute specificity of EBV for human CR2 through characterization of a panel of 24 human-murine chimeric receptors, all of which bind human C3dg. The results indicate that preferential binding of EBV to human CR2 is not due to unique amino acids that are capable of binding the virus, but reflects a distinct receptor conformation that can be achieved in murine CR2 with single amino acid substitutions in two discontinuous regions of the primary structure: replacement of proline at position 15 with the corresponding serine from human CR2, and elimination of a potential N-linked glycosylation site between SCR-1 and SCR-2. Furthermore, species-specific binding of EBV, OKB7, and 7G6 can all be manipulated through substitutions among residues 8-15, suggesting that this octapeptide is part of a structural determinant that is critical for binding of both viral and natural ligands to CR2.
Martin
D R
DR
Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Yuryev
A
A
Kalli
K R
KR
Fearon
D T
DT
Ahearn
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011951:Receptors, Complement / Q000378:metabolism*; D017464:Receptors, Complement 3d; D011991:Receptors, Virus / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship
D000944:Antigens, Differentiation, B-Lymphocyte; D011951:Receptors, Complement; D017464:Receptors, Complement 3d; D011991:Receptors, Virus