Interaction of β2-Glycoprotein 1 with Phosphatidylserine-Containing Membranes:  Ligand-Dependent Conformational Alterations Initiate Bivalent Binding

Hamdan, Randala; Maiti, Sourindra N.; Schroit, Alan J.

doi:10.1021/bi700621j

Cited by 24 publications

(25 citation statements)

References 44 publications

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“…The five domains are arranged like beads on a string, forming an elongated J-shaped molecule. In the fifth domain, the positively charged sequence CKNKEKKC and a nearby hydrophobic loop appear to be involved in the binding of the protein to negatively charged phospholipid membrane (19). A large number of evidence demonstrates that ß 2 GPI is the most common target for antiphospholipid antibodies (20).…”

Section: Discussionmentioning

confidence: 99%

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

Zhou¹

2009

Int J Mol Med

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Abstract. Growing evidence suggests that autoantibodies directly contribute to hypercoagulability in the antiphospholipid syndrome (APS). One proposed mechanism is the antibodyinduced expression of tissue factor (TF) by blood monocytes. Annexin A2 (ANX2), a mediator of cell surface-specific plasmin generation, was identified to mediate endothelial cell activation by anti-ß 2 -glycoprotein I (anti-ß 2 GPI) antibody. Our previous study suggested that ANX2 was also involved in anti-ß 2 GPI/ß 2 GPI-induced TF expression on monocytes. In the current study, it was further demonstrated that ß 2 GPI interacts with ANX2 not only in a cell-dependent form but also in a cell-free system. To further confirm the effects of ANX2 on anti-ß 2 GPI/ß 2 GPI-induced TF expression, an ANX2 cDNAcontaining vector was transfected into HEK 293T cells which had originally little ANX2, then cells were treated by anti-ß 2 GPI/ß 2 GPI complex. It was found that transfected HEK 293T cells could express more TF both at mRNA and protein levels than that of no-transfected cells. On the other hand, the TF expression was dramatically decreased in the THP-1 cells in which the ANX2 RNA interference was performed. In conclusion, these results indicate that ANX2 on cell surface functions as a mediator boosting TF expression on monocytes induced by anti-ß 2 GPI/ß 2 GPI complex, which is contributed to the thrombotic events in APS.

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Section: Discussionmentioning

confidence: 99%

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

Zhou¹

2009

Int J Mol Med

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“…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.…”

Section: Introductionmentioning

confidence: 99%

β2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator

Gropp

Weber

Reuter

et al. 2011

Blood

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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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“…Interactions between b2-gpI and ECs are initiated by lysine residues in the cofactor (17) associating with PLs on the membrane (18). This electrostatic symmetry needs to be reinforced by a sound link between 2 aa sequences, one in the cofactor and another in unknown receptors on the membrane.…”

mentioning

confidence: 99%

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Alard

Gaillard

Daridon

et al. 2010

The Journal of Immunology

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During the antiphospholipid syndrome, β2-gpI interacts with phospholipids on endothelial cell (EC) surface to allow the binding of autoantibodies. However, induced-pathogenic intracellular signals suggest that β2-gpI associates also with a receptor that is still not clearly identified. TLR2 and TLR4 have long been suspected, yet interactions between TLRs and β2-gpI have never been unequivocally proven. The aim of the study was to identify the TLR directly involved in the binding of β2-gpI on EC surface. β2-gpI was not synthesized and secreted by ECs in vitro, but rather taken up from FCS. This uptake occurred through association with TLR2 and TLR4 which partitioned together in the lipid rafts of ECs. After coimmunoprecipitation, mass-spectrometry identification of peptides demonstrated that TLR2, but not TLR4, was implicated in the β2-gpI retention. These results were further confirmed by plasmon resonance-based studies. Finally, siRNA were used to obtain TLR2-deficient ECs that lost their ability to bind biotinylated β2-gpI and to trigger downstream phosphorylation of kinases and activation of NFκB. TLR4 may upregulate TLR2 expression, thereby contributing to β2-gpI uptake. However, our data demonstrate that direct binding of β2-gpI on EC surface occurs through direct interaction with TLR2. Furthermore, signaling for anti–β2-gpI may be envisioned as a multiprotein complex concentrated in lipid rafts on the EC membrane.

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Interaction of β2-Glycoprotein 1 with Phosphatidylserine-Containing Membranes: Ligand-Dependent Conformational Alterations Initiate Bivalent Binding

Cited by 24 publications

References 44 publications

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytes

β2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

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