Homozygous deletion of a 84-kb genomic fragment in human chromosome 1 that encompasses the CFHR1 and CFHR3 genes represents a risk factor for hemolytic uremic syndrome (HUS) but has a protective effect in age-related macular degeneration (AMD). Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. This activity is distinct from complement factor H, and apparently factor H and CFHR1 control complement activation in a sequential manner. As both proteins bind to the same or similar sites at the cellular surfaces, the gain of CFHR1 activity presumably is at the expense of CFH-mediated function (inhibition of the C3 convertase). In HUS, the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases. IntroductionThe complement system is important for host innate and adaptive immunity and mounts a protective immune response to invading microbes. 1 The alternative complement pathway is spontaneously activated, and generates C3 convertases (C3bBb) that cleave the central component C3 to the anaphylactic peptide C3a and C3b. 2,3 C3b attached to a foreign surface binds factor B and generates the C3 convertase (C3bBb), which enhances further complement activation resulting in opsonization and phagocytosis of particles. Binding of an additional C3b molecule to the C3 convertase forms the C5 convertase (C3bBbC3b) of the alternative pathway. This convertase cleaves C5 and generates the potent chemoattractant C5a as well as C5b, which initiates the terminal complement pathway assembly. 4 C5b immediately undergoes conformational changes and binds C6 and C7 in a nonenzymatic manner. The assembled C5b67 complex is released from the convertase and attaches to lipid bilayers. Upon binding of C8 and C9, the lytic membrane attack complex (MAC) is formed. 3,5 Once activated, this powerful defense system is tightly controlled on host cell surfaces by both membrane-anchored and surface-attached soluble regulators. Proper and coordinated function of these regulators is essential for tissue integrity. Single gene mutations predispose to severe renal and retinal diseases, that is, hemolytic uremic syndrome (HUS; OMIM no. 235400), membranoproliferative glomerulonephritis type II (MPGN II; OMIM no. 609814), or age-related macular degeneration (AMD; OMIM no. 603075). 6,7 HUS is caused by occlusion of arterioles and capillaries in the kidney, due to endothelial cell and platelet damage. 8 MPGN II is a rare renal disease, with formation of dense deposits at the glomerular basement membrane and thickening of the peripheral capillary walls. 9 Similarly, the retinal disease AMD, which causes visual impairment of elderly people, is caused by deposits (drusen) that form on the Bruch membrane and le...

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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...

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