Molecular Structure of Apolipoproteins and Lipid-Protein Complexes.

Research project P 13872 Molekular Structure of Apolipoproteins Ruth PRASSEL 24.01.2000 Apolipoproteins are associated with circulating lipoproteins in human plasma and allow the redistribution of lipids and cholesterol from the arterial wall to other tissues. They exert benefical effects on systems involved in the development of atherosclerotic plaques or coronary heart diseases. They play an essential role in blood coagulation cascade and fibrinolysis. However, apolipoproteins may also be involved in the emergence and progression of various diseases. Two distinct apolipoprotein Glasses, namely b 2 glycoprotein 1 (b 2 GPl) and apolipoprotein AI (apoAI) will be subject of the proposed scientific program. The project aims to provide details on the underlying molecular events leading to an understanding of structure-function relationships manifesting the different biological activities of the apolipoproteins. The physiological role of b 2 GPI is only partly understood yet, evidence exists that it acts as natural anticoagulant in blood coagulation. b 2 GPl has recently obtained growing biomedical interest as it acts as cofactor for autoantibody binding. Via interactions with negatively charged phospholipids b 2 GPI becomes the major target of autoantibodies associated with pathological events such as antiphospholipid syndrome. The understanding of the fundamental mechanisms and structural requirements responsible for the differentiated functions of the protein are still missing. Thus, the envisaged achievement of the project is to construct a detailed three-dimensional structural model of b 2 GPI-species. This should allow the identification of specific protein domains involved in phospholipid and autoantibody binding. New insights into the pathogenic events underlying the clinical manifestations of autoimmune diseases such as lupus erythematosus or thrombosis shall be derived. Clinical evidence suggests that the anti-atherogenic activity of high density lipoprotein is mediated by apolipoprotein AI (apo AI). Little information is available on the physiological impact of conformational rearrangements of apo AI induced by lipid binding. One objective of the project is to construct a model of the three-dimensional structure of apo AI at different states of lipid interaction in order to build up the knowledge base for the design of novel pharmacological drugs for the treatment of atherosclerotic vascular diseases.