biophysical analysis of apolipoprotein e3 variants linked with development of type iii hyperlipoproteinemia生物物理分析载脂蛋白e3变异与iii型高脂蛋白血症.pdfVIP

Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia 1 2 3 3 1 Dimitra Georgiadou , Angeliki Chroni , Alexander Vezeridis , Vassilis I. Zannis , Efstratios Stratikos * 1 Protein Chemistry Laboratory, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens, Greece, 2 Institute of Biology, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens, Greece, 3 Molecular Genetics, Departments of Medicine and Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America Abstract Background: Apolipoprotein E (apoE) is a major protein of the lipoprotein transport system that plays important roles in lipid homeostasis and protection from atherosclerosis. ApoE is characterized by structural plasticity and thermodynamic instability and can undergo significant structural rearrangements as part of its biological function. Mutations in the 136–150 region of the N-terminal domain of apoE, reduce its low density lipoprotein (LDL) receptor binding capacity and have been linked with lipoprotein disorders, such as type III hyperlipoproteinemia (HLP) in humans. However, the LDL-receptor binding defects for these apoE variants do not correlate well with the severity of dyslipidemia, indicating that these variants may carry additional properties that contribute to their pathogenic potential. Methodology/Principal Findings: In this study we examined whether three type III HLP predisposing apoE3 variants, namely R136S, R145C and K146E affect the biophysical properties of the protein. Circular dichroism (CD) spectroscopy revealed that