Crystal structure of human β2-glycoprotein I:: implications for phospholipid binding and the antiphospholipid syndrome

被引:248
作者
Schwarzenbacher, R
Zeth, K
Diederichs, K
Gries, A
Kostner, GM
Laggner, P
Prassl, R
机构
[1] Austrian Acad Sci, Inst Biophys & Xray Struct Res, A-8020 Graz, Austria
[2] Graz Univ, Inst Physiol, A-8010 Graz, Austria
[3] Graz Univ, Inst Med Biochem, A-8010 Graz, Austria
[4] MPI Biochem, Dept Mol Struct Biol, D-82152 Martinsried, Germany
[5] Univ Konstanz, Fac Biol, D-78457 Constance, Germany
关键词
apolipoprotein H (ApoH); complement control protein; beta 2-glycoprotein I; short consensus repeat; sushi domain;
D O I
10.1093/emboj/18.22.6228
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The high affinity of human plasma beta 2-glycoprotein I (beta(2)GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. beta(2)GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the beta(2)GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans, The structure reveals four complement control protein modules and a distinctly folding fifth C-terminal domain arranged like beads on a string to form an elongated J-shaped molecule. Domain V folds into a central beta-spiral of four antiparallel beta-sheets with two small helices and an extended C-terminal loop region, It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313-316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances, The beta(2)GPI structure reveals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid-binding capacity of beta(2)GPI.
引用
收藏
页码:6228 / 6239
页数:12
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