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: 10667541
• 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/10667541
• 关键词: Address; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Attenuated; Binding; Binding Sites; Biological Assay; Brain; Cardiovascular Diseases; Chemicals; Cholesterol; Cholesterol Esters; Circulation; Complex; Conserved Sequence; Cryoelectron Microscopy; 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; Phosphatidylcholine-Sterol O-Acyltransferase; 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; Visualization; Work; cofactor; crosslink; design; experimental study; fish eye disease; interest; lecithin cholesterol acyltransferase deficiency; 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).

LCAT：胆固醇酰基转移酶（LCAT）催化脂肪酸的酯化， 胆固醇，并负责人体内大部分胆固醇酯（CE） 流通其活性被辅因子载脂蛋白如 HDL中的载脂蛋白（apo）A-I和LDL/VLDL和脑脂蛋白中的apoE。虽然这 辅因子的关系已经知道了几十年，我们的理解如何载脂蛋白 激活LCAT仍然有限。我们的初步工作表明，LCAT与两个 在apoA-I分子中由螺旋4组成的apoA-I内的镜像对接位点 和相对分子的螺旋6。当此注册表中断时，LCAT仍然可以绑定HDL 但不再催化CE形成。我们假设这些对接点使LCAT 并且可以形成导管，通过该导管颗粒 进入芯以沉积CE。此外，我们怀疑这些网站直接 通过特异性识别序列将胆固醇底物转移到LCAT相互作用的位点。我们 我也相信，apoA-II，另一种高密度脂蛋白载脂蛋白，破坏了这一点， 相互作用以降低LCAT活性。利用我们开发的新实验工具， 实验室，我们将; 1）定义apoA-I激活LCAT和LCAT的分子机制 这些相互作用位点的作用，2）确定apoA-II如何减弱LCAT反应和3） 明确apoE刺激LCAT的机制。这项工作将回答近50年 载脂蛋白如何增强LCAT介导血浆胆固醇的能力 酯化反应此外，我们将把这些知识转化为设计新颖的双螺旋 可形成治疗LCAT遗传部分缺陷个体的基础的肽 鱼眼病（Fish Eye Disease，FED）

项目成果

The Difference Between High Density Lipoprotein Subfractions and Subspecies: an Evolving Model in Cardiovascular Disease and Diabetes.

高密度脂蛋白亚组分和亚种之间的差异：心血管疾病和糖尿病的进化模型。

• DOI: 10.1007/s11883-021-00925-4
• 发表时间: 2021-03-27
• 期刊: Current atherosclerosis reports
• 影响因子: 5.8
• 作者: Davidson WS;Cooke AL;Swertfeger DK;Shah AS
• 通讯作者: Shah AS

The HDL Proteome Watch: Compilation of studies leads to new insights on HDL function.

• DOI: 10.1016/j.bbalip.2021.159072
• 发表时间: 2022-03
• 期刊: Biochimica et biophysica acta. Molecular and cell biology of lipids
• 作者: Davidson WS;Shah AS;Sexmith H;Gordon SM
• 通讯作者: Gordon SM