Crystal structure of human beta 2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome

The high affinity of human plasma beta 2-glycoprotein I (beta(2)GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids dete rmines its implication in a variety of physiological pathways, including bl ood coagulation and the immune response. beta(2)GPI is considered to be a c ofactor for the binding of serum autoantibodies from antiphospholipid syndr ome (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 fo ur glycans, The structure reveals four complement control protein modules a nd a distinctly folding fifth C-terminal domain arranged like beads on a st ring 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 resid ues LAFW (313-316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances, The beta(2)GPI structure re veals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phosphol ipid-binding capacity of beta(2)GPI.