Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome.
The high affinity of human plasma beta2-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.
Schwarzenbacher
R
R
Institute of Biophysics and X-ray Structure Research, Austrian Academy of Sciences, Steyrergasse 17/6, A-8020 Graz.
Zeth
K
K
Diederichs
K
K
Gries
A
A
Kostner
G M
GM
Laggner
P
P
Prassl
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry; D001665:Binding Sites; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004330:Drosophila; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D053482:beta 2-Glycoprotein I
D001053:Apolipoproteins; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I