TY - JOUR
T1 - Antigenic structures recognized by anti-β2-glycoprotein I auto-antibodies
AU - Kasahara, Hideki
AU - Matsuura, Eiji
AU - Kaihara, Keiko
AU - Yamamoto, Daisuke
AU - Kobayashi, Kazuko
AU - Inagaki, Junko
AU - Ichikawa, Kenji
AU - Tsutsumi, Akito
AU - Yasuda, Shinsuke
AU - Atsumi, Tatsuya
AU - Yasuda, Tatsuji
AU - Koike, Takao
N1 - Funding Information:
This work was supported in part by a grant for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by grants from the Ministry of Health and Welfare of Japan. We thank M. Ohara for pertinent comments.
PY - 2005/12
Y1 - 2005/12
N2 - β2-Glycoprotein I (β2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of β2-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-β2-GPI auto-antibodies to solid-phase β2-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-β2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.
AB - β2-Glycoprotein I (β2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of β2-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-β2-GPI auto-antibodies to solid-phase β2-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-β2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.
KW - Anti-phospholipid antibody
KW - Anti-phospholipid syndrome
KW - B cell epitope
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U2 - 10.1093/intimm/dxh330
DO - 10.1093/intimm/dxh330
M3 - Article
C2 - 16221723
AN - SCOPUS:28744436571
VL - 17
SP - 1533
EP - 1542
JO - International Immunology
JF - International Immunology
SN - 0953-8178
IS - 12
ER -