Glycopeptide profiling of beta-2-glycoprotein I by mass spectrometry reveals attenuated sialylation in patients with antiphospholipid syndrome

Kondo, Akira; Miyamoto, Toshiaki; Yonekawa, Osamu; Giessing, Anders; Østerlund, Eva Christina; Jensen, Ole N.

doi:10.1016/j.jprot.2009.08.007

Cited by 35 publications

(36 citation statements)

References 28 publications

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“…12 The conformational change that is induced in ␤ 2 GPI after binding to phospholipids should interfere with the intramolecular interaction of the carbohydrate side chain with the epitope for the antibodies, which subsequently results in the exposure of the epitope for the antibodies. This idea was further elaborated by Kondo et al 38 who demonstrated increased sialylation of the glycan structures of ␤ 2 GPI of APS patients, suggesting an altered intramolecular interaction and conformational instability of ␤ 2 GPI in patients. At the moment, we have no information whether differences in sialylation of carbohydrate side chains of ␤ 2 GPI facilitate the conversion between the open and circular conformation by anti-␤ 2 GPI antibodies.…”

Section: Discussionmentioning

confidence: 83%

β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome

Ağar

Mörgelin

et al. 2010

Blood

239

269

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The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that ␤ 2 -glycoprotein I (␤ 2 GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize ␤ 2 GPI when bound to anionic surfaces and not in solution. We showed that ␤ 2 GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of ␤ 2 GPI. By changing pH and salt concentration, we were able to convert the conformation of ␤ IntroductionThe antiphospholipid syndrome (APS) is defined as the presence of antiphospholipid antibodies in the blood of patients with thrombosis or fetal loss. The APS is one of the most common causes of acquired thrombophilia, 1 especially at younger age. In 1990, it was shown that the so-called antiphospholipid antibodies do not recognize phospholipids directly but they interact with phospholipids via the plasma protein ␤ 2 -glycoprotein I (␤ 2 GPI). [2][3][4] However, the discovery of ␤ 2 GPI as target for the autoantibodies did not provide a more in-depth knowledge on the underlying cause of the syndrome. It was unclear which metabolic pathway was disturbed by the autoantibodies because no physiologic function has convincingly been ascribed to ␤ 2 GPI to date. Nevertheless, as antibodies against ␤ 2 GPI can induce thrombosis in animal models, 5-7 the protein ␤ 2 GPI must hold an important functional clue to our understanding of the syndrome.␤ 2 GPI is a highly abundant 43-kDa protein that circulates at a concentration of approximately 200 g/mL. ␤ 2 GPI consists of 326 amino acids arranged in 5 short consensus repeat domains. 8,9 The first 4 domains contain 60 amino acids each, whereas the fifth domain has a 6-residue insertion and an additional 19-amino acid C-terminal extension. The extra amino acids are responsible for the formation of a large positively charged patch within the fifth domain of ␤ 2 GPI 10 that forms the binding site for anionic phospholipids. The anti-␤ 2 GPI antibodies that recognize an epitope located in the first domain correlate better with the thrombotic complications than antibodies directed against other domains. 11-13 Antibodies directed against ␤ 2 GPI have become one of the serologic markers characterizing the APS. 14 After binding to anionic surfaces, ␤ 2 GPI exposes a cryptic epitope that is recognized by the autoantibodies present in the APS. 11,12,15,16 These antibodies only recognize ␤ 2 GPI when it is bound to a surface and do not recognize ␤ 2 GPI in solution. Moreover, no circulating immune complexes between antibodies and ␤ 2 GPI have been detected in patient plasmas. 17 This seems not to be the result of clearance of these complexes from plasma because plasma levels of ␤ 2 GPI in antiphospholipid patients are the same as plasma levels of ␤ 2 GPI in healthy persons. 18 The crystal st...

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Section: Discussionmentioning

confidence: 83%

β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome

Ağar

Mörgelin

et al. 2010

Blood

239

269

View full text Add to dashboard Cite

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“…Although the amino acid composition of β2-GPI indicates that the mouse protein is more basic (theoretical p I = 8.62) than the human protein (theoretical p I = 8.37), 2D gel analysis shows that the average actual p I of the mouse protein is more acidic suggesting that the amino acid differences are compensated by negative charges introduced through post-translational modifications. The human native β2-GPI is decorated with a variable number of sialic acid residues (Kondo et al, 2009; Schousboe, 1983). The addition of variable numbers of sialic acid residues and/or other carbohydrate chains would explain the multiple isoforms found on the 2D gel.…”

Section: Discussionmentioning

confidence: 99%

Human β2-glycoprotein I attenuates mouse intestinal ischemia/reperfusion induced injury and inflammation

Tomasi

Hiromasa

Pope

et al. 2012

Molecular Immunology

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Intestinal ischemia-reperfusion (IR)-induced injury results from a complex cascade of inflammatory components. In the mouse model of intestinal IR, the serum protein, β2-glycoprotein I (β2-GPI) binds to the cell surface early in the cascade. The bound β2-GPI undergoes a conformational change which exposes a neoantigen recognized by naturally occurring antibodies and initiates the complement cascade. We hypothesized that providing additional antigen with exogenous β2-GPI would alter IR-induced tissue injury. Administration of human but not mouse β2-GPI attenuated IR-induced tissue damage and prostaglandin E2 production indicating a physiological difference between β2-GPI isolated from the two species. To investigate whether structural features were responsible for this physiological difference, we compared the chemical, physical and biochemical properties of the two proteins. Despite possessing 76% amino acid identity and 86% sequence homology, we found that mouse β2-GPI differs from the human protein in size, carbohydrate chain location, heterogeneity and secondary structural content. These data suggest that the structural differences result in mouse Ab recognition of soluble human but not mouse β2-GPI and attenuated IR-induced injury. We conclude that caution should be exercised in interpreting results obtained by using human β2-GPI in a mouse model.

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“…The exposed epitopes can possibly be recognized by the autoantibody and lead to pathogenic events such as vascular thrombosis or pregnancy morbidity. Small-angle X-ray scattering experiments revealed that the N-linked carbohydrate structures in b2GPI are important for maintaining/stabilizing the conformation of the protein [31,32]. http://www.sciencedirect.com/science/article/ pii/S1874391909002462-ref_bib18.…”

Section: Discussionmentioning

confidence: 99%

“…It was further shown that changes of the distribution of glycans in b2GPI can leads to change of the interaction between the glycan chain and epitope in APS patients. This change could easily trigger access of anti-b2GPI Abs to the cryptic epitope, thereby leading to an autoimmune reaction and APS symptoms [32]. The importance of glycan chains on the b 2 GPI molecule is further exemplified by studies…”

Section: Discussionmentioning

confidence: 99%

Anti-GalNAcβ: A novel anti-glycan autoantibody associated with pregnancy loss in women with antiphospholipid syndrome and in a mouse experimental model

Blank

Krause

Dotan³

et al. 2012

Journal of Autoimmunity

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Glycopeptide profiling of beta-2-glycoprotein I by mass spectrometry reveals attenuated sialylation in patients with antiphospholipid syndrome

Cited by 35 publications

References 28 publications

β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome

β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome

Human β2-glycoprotein I attenuates mouse intestinal ischemia/reperfusion induced injury and inflammation

Anti-GalNAcβ: A novel anti-glycan autoantibody associated with pregnancy loss in women with antiphospholipid syndrome and in a mouse experimental model

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