Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair
Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair
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DOI：
10.1038/88556
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发表时间：
2001-06-01
期刊：
影响因子：
--
通讯作者：
Blacklow, SC
中科院分区：
文献类型：
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作者：
Jeon, H;Meng, WY;Blacklow, SC
低密度脂蛋白受体（LDLR）是细胞摄取胆固醇携带颗粒的主要机制。在低pH值下参与受体再循环和脂蛋白释放的LDLR区域包含一对钙结合EGF样模块，随后是一系列6个YWTD重复序列和第三个EGF样模块。跨越YWTD重复序列及其两个侧翼EGF模块的受体片段在1.5埃分辨率下的晶体结构揭示，YWTD重复序列形成六叶β-螺旋桨，其紧密地包装在C-末端EGF模块上，而螺旋桨之前的EGF模块在晶体中是无序的。导致遗传疾病家族性高胆固醇血症（FH）的LDLR的许多点突变改变侧链，所述侧链在内部和螺旋桨叶片之间形成保守的包装和氢键相互作用。FK突变的第二个子集位于螺旋桨和C-末端EGF模块之间的界面处，这表明维持结构域间界面的完整性的结构要求。
The low-density lipoprotein receptor (LDLR) is the primary mechanism for uptake of cholesterol-carrying particles into cells. The region of the LDLR implicated in receptor recycling and lipoprotein release at low pH contains a pair of calcium-binding EGF-like modules, followed by a series of six YWTD repeats and a third EGP-like module. The crystal structure at 1.5 Angstrom resolution of a receptor fragment spanning the YWTD repeats and its two flanking EGF modules reveals that the YWTD repeats form a six-bladed Beta-propeller that packs tightly against the C-terminal EGF module, whereas the EGF module that precedes the propeller is disordered in the crystal. Numerous point mutations of the LDLR that result in the genetic disease familial hypercholesterolemia (FH) alter side chains that form conserved packing and hydrogen bonding interactions in the interior and between propeller blades. A second subset of FK mutations are located at the interface between the propeller and the C-terminal EGF module, suggesting a structural requirement for maintaining the integrity of the interdomain interface.