Energetics-Structure-Function Relationship in Lipoproteins

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

Our long-term goal is to determine the energetic-structure-function relationship in apolipoproteins and[unreadable] lipoproteins to gain a better insight into the molecular mechanisms of lipoprotein action in normal and in[unreadable] atherosclerotic states. The emphasis is on the folding, structure and stability of apolipoproteins in solution[unreadable] and on lipoproteins, particularly on model discoidal HDL and human plasma or reconstituted LDL. The[unreadable] balance between HDL, LDL and their subclasses in plasma determines the probability of developing[unreadable] cardiovascular disease and stroke. Structural stability of lipoproteins is essential for their functions, yet the[unreadable] precise mechanism of their stabilization is unknown. Furthermore, HDL and LDL are extensively re-modeled[unreadable] by plasma factors during metabolism; for example, LDL fusion in the arterial wall is a key event in early[unreadable] atherosclerosis. However, the molecular mechanisms of HDL and LDL remodeling and fusion are not wellunderstood.[unreadable] Our research is aimed at detailed understanding of the energetic and structural basis underlying[unreadable] stability and re-modeling of HDL and LDL. Our preliminary studies of reconstituted discoidal HDL have[unreadable] revealed a novel kinetic mechanism of lipoprotein stabilization; they showed that lipoprotein destabilization[unreadable] and protein dissociation lead to particle fusion that involves high energy barriers. We demonstrated that a[unreadable] similar fusion-based kinetic mechanism confers stability to plasma HDL and LDL, and thus provides a[unreadable] universal natural strategy for lipoprotein stabilization. In the proposed work we will obtain detailed molecular[unreadable] determinants for the kinetic stability of discoidal HDL. The focus will be on the role of protein size,[unreadable] hydrophobicity, charge residue distribution, and lipid composition in the disks stability, with an emphasis on[unreadable] apoA-1-based proteins and peptides. Discoidal HDL of controlled composition will be reconstituted and[unreadable] analyzed by using an integrated spectroscopic, calorimetric, and electron microscopic approach. The kinetics[unreadable] of protein-lipid association, which will be analyzed by absorption and circular dichroism spectroscopy, will[unreadable] help to determine the role of the protein primary and secondary structure on the lipid binding pathway.[unreadable] Molecular determinants for LDL stability and fusion will be obtained, with an emphasis on the effects of[unreadable] protein and lipid oxidation, lipid composition, and apoB C-terminal truncations on the structure and stability of[unreadable] plasma or reconstituted lipoproteins. The energetic and structural analysis of HDL and LDL, such as this[unreadable] proposal, may lead to identification of compounds that promote or inhibit pro-atherogenic lipoprotein[unreadable] transformations such as fusion, and thereby help to develop new therapies for coronary artery disease and[unreadable] other lipoprotein-related disorders. Comparative studies of antifusogenic effects of apolipoproteins and[unreadable] peptides may also help to design apolipoprotein-based peptides with optimized antiviral properties, while[unreadable] identification of key determinants for LDL stability may help to design LDL-based drug carriers.