Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies.
Beta2-glycoprotein I (beta2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D193-K246, D222-K317 and E228-K308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta2-GPI auto-antibodies to solid-phase beta2-GPI was significantly reduced either by L replacement for W235, a common amino acid component for the epitopes, or by V replacement for all of D193, D222 and E228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W235 and that epitope spreading occurred in the region surrounding W235. Thus, epitopic structures recognized by anti-beta2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.
Kasahara
Hideki
H
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Matsuura
Eiji
E
Kaihara
Keiko
K
Yamamoto
Daisuke
D
Kobayashi
Kazuko
K
Inagaki
Junko
J
Ichikawa
Kenji
K
Tsutsumi
Akito
A
Yasuda
Shinsuke
S
Atsumi
Tatsuya
T
Yasuda
Tatsuji
T
Koike
Takao
T
D019943:Amino Acid Substitution; D017153:Antibodies, Anticardiolipin / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D053482:beta 2-Glycoprotein I
D017153:Antibodies, Anticardiolipin; D018985:Epitopes, B-Lymphocyte; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I