Grant number

2796987

Primary Investigator

Professor Paul Dalby

Funder

Medical Research Foundation 

Duration

2019-09-27    2020-01-01    2022-12-31

Project description

Beta-2-Glycoprotein I is a ubiquitous protein present in human serum at a concentration of 0.2 mg/ml, it has been detected in tissue across the body including the brain, placenta, eyes and heart in both health and disease. β2GPI is unique in structure, it can adopt 2 disparate structures: either a J shaped “open” structure of an O shaped “closed” structure. Although many proteins can have different structures associated with activities, Zymmogens or tissue factor for example, β2GPI is unique in having multiple methods by which it changes structure, however, it is unknown if one method predominates. Various roles have been vaunted for β2GPI including in the regulation of complement and coagulation, however it is still unknown what the major role for β2GPI in the body is. β2GPI is unusual as it has the ability to both up and down regulate complement and coagulation, however, how these opposing roles are controlled is unknown. The roles become more interesting when considered in the context of Antiphospholipid Syndrome, an autoimmune disorder for which β2GPI is the main antigenic target. APS patients develop antibodies to β2GPI and commonly present with miscarriages and thromboses, showing antibodies to β2GPI may dysregulate the role of β2GPI in these systems. The way in which β2GPI differs to allow the development of these antibodies or indeed the effect of the antibodies on the structure of β2GPI is also unknown. I propose an ambitious study attempting to ally the structural changes in β2GPI with its different activities in the body. I will study β2GPI purified from healthy controls and APS patients and study the differences in structure and glycosylation to question why APS patients develop antibodies. I will further modify commercially available β2GPI to study the effect of reduction, deglycosylation and plasmin cleavage on the structure of β2GPI before testing these variants, and β2GPI purified from APS patients in assays of complement, coagulation and antibody binding to ascertain what effect the structural changes have had on the activity of β2GPI. This would be the first interdisciplinary study of β2GPI attempting to use both structural/nanostructural techniques and functional testing to understand the role of structure on the function of β2GPI