The role of beta-2-glycoprotein I in health and disease associating structure with function: More than just APS

Abstract

Beta-2-Glycoprotein I (β2GPI) plays a number of essential roles throughout the body. β2GPI, C-reactive protein and thrombomodulin are the only three proteins that possess the dual capability to up and down regulate the complement and coagulation systems depending upon external stimulus. Clinically, β2GPI is the primary antigen in the autoimmune condition antiphospholipid syndrome (APS), which is typically characterised by pregnancy morbidity and vascular thrombosis. This protein is also capable of adopting at least two distinct structural forms, but it has been argued that several other intermediate forms may exist. Thus, β2GPI is a unique protein with a key role in haemostasis, homeostasis and immunity. In this review, we examine the genetics, structure and function of β2GPI in the body and how these factors may influence its contribution to disease pathogenesis. We also consider the clinical implications of β2GPI in the diagnosis of APS and as a potentially novel therapeutic target.

Keywords: Antiphospholipid syndrome; Beta-2-glycoprotein I; Coagulation; Complement; Structural biochemistry.

Fig. 1

Proposed structural states of β2GPI and the transition to cellular binding. The schematic above demonstrates the potential interactions between cell surfaces, β2GPI and antibodies in APS. The proposed schemes are intensely debated in the field. The top scheme shows antibody binding to a closed β2GPI with this causing β2GPI to open and bind cell membranes. The middle scheme shows β2GPI opening due to environmental factors with an antibody later binding. The bottom scheme shows circular β2GPI binding a cell membrane, opening and dimerization by an antibody. Debate exists as to which of these schemes is the most physiologically relevant.

Fig. 2

Coagulation and Complement Interactions. This diagram shows the varying contrasting interactions of CRP, thrombomodulin and beta-2-glycoprotein I. Red arrows indicate upregulation in the presence of β2GPI whilst red arrows with a circular ending indicate inhibition in the presence of β2GPI. Orange arrows represent upregulations in the presence of thrombomodulin and green arrows upregulation in the presence of CRP. The blue lines represent physiological interactions which may be altered by the proteins. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)