The J-elongated conformation of b2-glycoprotein I predominates in solution: implications for our understanding of antiphospholipid syndrome
| Autor: | Mathivanan Chinnaraj, Zhiwei Chen, Francesco Tedesco, Vittorio Pengo, Eliza A. Ruben, William Planer, Vincenzo De Filippis, Xiaobing Zuo, Nicola Pozzi, Paolo Macor, Ravi Kumar Alluri, Keith R. McCrae |
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| Přispěvatelé: | Ruben, E., Planer, W., Chinnaraj, M., Chen, Z., Zuo, X., Pengo, V., de Filippis, V., Alluri, R. K., Mccrae, K. R., Macor, P., Tedesco, F., Pozzi, N. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
single-molecule biophysics Antiphospholipid single-molecule biophysic Biochemistry Mutagenesi structure-function law.invention lipid–protein interaction HEK293 Cell immune system diseases law Cricetinae structural biology thrombosi Chemistry autoimmunity X-ray crystallography antiphospholipid syndrome autoimmune disease beta-2 glycoprotein I coagulation complement system protein–protein interaction thrombosis Animals Antibodies Antiphospholipid HEK293 Cells Humans Kinetics Mutagenesis Protein Domains beta 2-Glycoprotein I Antiphospholipid Syndrome Receptor–ligand kinetics Protein Structure and Folding Recombinant DNA Human Protein Domain Protein domain Antibodies Protein–protein interaction 03 medical and health sciences Beta 2-Glycoprotein I Molecular Biology Kinetic 030102 biochemistry & molecular biology Animal Cell Biology Complement system 030104 developmental biology Structural biology Biophysics |
| Zdroj: | J Biol Chem |
| Popis: | β(2)-Glycoprotein I (β(2)GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound β(2)GPI to that in solution. β(2)GPI exists in two almost equally populated redox states: oxidized, in which all the disulfide bonds are formed, and reduced, in which one or more disulfide bonds are broken. Furthermore, β(2)GPI can adopt multiple conformations (i.e. J-elongated, S-twisted, and O-circular). While strong evidence indicates that the J-form is the structure bound to aPLs, which conformation exists and predominates in solution remains controversial, and so is the conformational pathway leading to the bound state. Here, we report that human recombinant β(2)GPI purified under native conditions is oxidized. Moreover, under physiological pH and salt concentrations, this oxidized form adopts a J-elongated, flexible conformation, not circular or twisted, in which the N-terminal domain I (DI) and the C-terminal domain V (DV) are exposed to the solvent. Consistent with this model, binding kinetics and mutagenesis experiments revealed that in solution the J-form interacts with negatively charged liposomes and with MBB2, a monoclonal anti-DI antibody that recapitulates most of the features of pathogenic aPLs. We conclude that the preferential binding of aPLs to phospholipid-bound β(2)GPI arises from the ability of its preexisting J-form to accumulate on the membranes, thereby offering an ideal environment for aPL binding. We propose that targeting the J-form of β(2)GPI provides a strategy to block pathogenic aPLs in APS. |
| Databáze: | OpenAIRE |
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