The structural basis for cholesterol esterification in human plasma

人血浆中胆固醇酯化的结构基础

• 批准号: 10450679
• 负责人: W Sean Davidson
• 金额: $ 48.66万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450679
• 关键词: Address; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Attenuated; Binding; Binding Sites; Biological Assay; Blood Circulation; Brain; Cardiovascular Diseases; Chemicals; Cholesterol; Cholesterol Esters; Complex; Cryoelectron Microscopy; Crystallization; Deposition; Disease; Docking; Electron Microscopy; Epitopes; Equilibrium; Esterification; Face; Fatty Acids; Fatty acid glycerol esters; Fluorescence; Genetic; Genetic Diseases; High Density Lipoproteins; Human; Image; Individual; Inflammatory; Kidney Failure; Knowledge; Laboratories; Lecithin; Lipids; Lipoproteins; Location; Low-Density Lipoproteins; Mass Spectrum Analysis; Mediating; Metabolism; Molecular; Molecular Conformation; Mutagenesis; Nucleosome Core Particle; Organ; Participant; Peptides; Phospholipase; Plasma; Play; Production; Proteins; Reaction; Recombinants; Registries; Roentgen Rays; Role; Running; Scientist; Series; Site; Site-Directed Mutagenesis; Structural Models; Structure; Surface; Surface Plasmon Resonance; System; Testing; Therapeutic; Transferase; Translating; Triglycerides; Very low density lipoprotein; Work; cofactor; crosslink; design; experimental study; fish eye disease; interest; novel; particle; rational design; tool

Lecithin:cholesterol acyl transferase (LCAT) catalyzes the esterification of a fatty acid to cholesterol and is responsible for the majority of cholesteryl ester (CE) in the human circulation. Its activity is dramatically enhanced by cofactor apolipoproteins such as apolipoprotein (apo)A-I in HDL and apoE in LDL/VLDL and brain lipoproteins. While this cofactor relationship has been known for decades, our understanding of how apolipoproteins activate LCAT remains limited. Our preliminary work has shown that LCAT interacts with two mirror image docking sites within apoA-I that are composed of helix 4 in one apoA-I molecule and helix 6 of the opposing molecule. When this registry is disrupted, LCAT can still bind HDL but no longer catalyzes CE formation. We hypothesize that these docking sites orient LCAT with respect to the lipid faces of HDL particles and may form a conduit by which the particle core is accessed for deposition of CE. Additionally, we suspect that these sites direct the cholesterol substrate to the site of LCAT interaction via specific recognition sequences. We also believe that apoA-II, another highly abundant HDL apolipoprotein, disrupts this interaction to reduce LCAT activity. Leveraging new experimental tools developed in our laboratory, we will; 1) define the molecular mechanism for apoA-I activation of LCAT and the role of these interaction sites, 2) determine how apoA-II attenuates the LCAT reaction and 3) define the mechanism behind apoE stimulation of LCAT. This work will answer nearly 50 year old questions about how apolipoproteins enhance LCAT’s ability mediate plasma cholesterol esterification. In addition, we will translate this knowledge into the design of novel bi-helical peptides that may form a basis for treating individuals with genetic partial deficiencies of LCAT activity such as Fish Eye Disease (FED).

卵磷脂：胆固醇酰基转移酶（LCAT）催化脂肪酸酯化成