The human plasma protein  2 -glycoprotein I ( 2 -GPI) is the major target of autoantibodies associated with antiphospholipid syndrome. However, the biologic function of this abundant protein is still unclear. Here we identify  2 -GPI as a complement regulator.  2 -GPI circulates in the plasma in an inactive circular form. On surface binding, such as to apoptotic cells,  2 -GPI changes conformation to an elongated form that acquires C3/C3b binding activities.  2 -GPI apparently changes conformation of C3, so that the regulator factor H attaches and induces subsequent degradation by the protease factor I.  2 -GPI also mediates further cleavage of C3/C3b compared with factor H alone. Our data provide important insights into innate immune regulation by plasma protein  2 -GPI, which may be exploited in the prevention and therapy of autoimmune disease antiphospholipid syndrome.
Introduction 2 -glycoprotein I ( 2 -GPI), also termed apolipoprotein H, 1 is a 50-kDa glycosylated human plasma protein with a concentration of 200 g/mL (4M) 2 that also associates with lipoprotein particles. 3 In the autoimmune disease antiphospholipid syndrome (APS), autoantibodies to  2 -GPI are identified. [4][5][6] APS is characterized by recurrent vascular thrombosis and pregnancy loss; and in pregnant women,  2 -GPI autoantibodies trigger severe complications, resulting in miscarriage, intrauterine growth restriction, and fetal death. 7-9  2 -GPI displays anticoagulant activity and inhibits the contact activation of the intrinsic coagulation pathway, 10 platelet prothrombinase activity 11 and adenosine diphosphate-induced platelet aggregation. 12 In addition,  2 -GPI also exerts antiangiogenic and antitumor activities. 13,14 Despite these activities, the main function of  2 -GPI is unknown. 2 -GPI is composed, like complement factor H and factor H-related protein 1, of consecutive short consensus repeat elements (SCRs), also called complement control protein modules, each approximately 60 amino acids in size. 15 These repeats are frequently found in proteins with complement-regulatory functions. The fifth domain of  2 -GPI has a modified structure, as it contains a 6-residue insertion and an extra 20-amino acid-long mobile tail. Together, these additional amino acids form a binding site for negatively charged, anionic phospholipids, such as phosphatidylserine or cardiolipin, 16,17 which are exposed on apoptotic or necrotic cells. Recently, Agar et al 18 identified 2 conformations of  2 -GPI: a circular inactive form of  2 -GPI in the plasma and an elongated, active one when  2 -GPI is bound to surfaces. The circular form results from internal interaction of the N-terminal SCRI with the C-terminal SCRV of  2 -GPI. This interaction is disrupted by binding of  2 -GPI to surfaces, which generates the elongated conformation. 18 The crystal structure of  2 -GPI shows the open, J-shaped form of  2 -GPI. 19,20 As the  2 -GPI protein function is unclear, we aimed to identify the role of this human plasma protein. Given t...
