Structural Biology of Scavenger Receptors

清道夫受体的结构生物学

• 批准号: 6828629
• 负责人: Jeffrey C Boyington
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6828629
• 关键词: X ray crystallography; antigen presentation; atherosclerosis; biological signal transduction; cell surface receptors; crystallization; ligands; lipid transport; low density lipoprotein; oxidized lipid; phagocytes; protein structure function; receptor binding; scavenger receptor

Scavenger receptors (SRs), commonly expressed on the surfaces of phagocytes, are a structurally diverse group of receptors that share a common theme of binding to modified lipoproteins. Biologically, SRs are important for the detection and clearance of a wide array of potentially harmful ligands such as oxidatively modified proteins and lipoproteins, advanced glycation end products (AGE), oxidatively modified phospholipids, bacterial DNA, anionic polymers, apoptotic cells, bacterial cell wall components, and foreign particles such as silica dust and asbestos. Particular attention has been focused on oxidized low density lipoprotein (oxLDL), an SR ligand thought to be significant in the pathology of atherosclerosis, oxLDL-binding SRs and on SRs involved in the transport of lipids across the cell membrane. We have begun structural investigations of three key SRs important in both of these areas in addition to a protein SR ligand involved in antigen presentation. Our goal is to analyze these receptors and receptor/ligand complexes by x-ray crystallography as a means to understand the mechanisms of ligand recognition and subsequent signal transduction through the plasma membrane. This information is critical to elucidating how phagocytes interface with and respond to both endogenous and environmental challenges. Subcloning, design of multiple constructs, and receptor expression studies in E coli are currently underway.

清道夫受体 (SR) 通常在吞噬细胞表面表达，是一组结构多样的受体，它们具有与修饰脂蛋白结合的共同主题。从生物学角度来看，SR 对于检测和清除多种潜在有害配体非常重要，例如氧化修饰蛋白和脂蛋白、晚期糖基化终产物 (AGE)、氧化修饰磷脂、细菌 DNA、阴离子聚合物、凋亡细胞、细菌细胞壁成分，以及硅尘和石棉等异物颗粒。特别关注的是氧化低密度脂蛋白 (oxLDL)，一种被认为在动脉粥样硬化病理学中具有重要意义的 SR 配体、oxLDL 结合 SR 以及参与脂质跨细胞膜转运的 SR。除了参与抗原呈递的蛋白质 SR 配体之外，我们还开始对在这两个领域都很重要的三个关键 SR 进行结构研究。我们的目标是通过 X 射线晶体学分析这些受体和受体/配体复合物，作为了解配体识别和随后通过质膜的信号转导机制的手段。这些信息对于阐明吞噬细胞如何与内源性和环境挑战相互作用并做出反应至关重要。目前正在进行亚克隆、多种构建体的设计以及大肠杆菌中的受体表达研究。