Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.
Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.
复制标题
分子内接触对 LDL 受体脂蛋白摄取的作用。
DOI：
10.1016/j.bbalip.2011.04.002
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Michaely,Peter
中科院分区：
文献类型：
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作者：
Zhao,Zhenze;Michaely,Peter
LDL受体（LDLR）是一种内吞受体，在清除循环中致动脉粥样硬化脂蛋白中起主要作用。在内吞过程中，LDLR首先在细胞表面结合脂蛋白，然后运输到内体，在那里受体释放结合的脂蛋白。释放是酸依赖性的，并且与受体内分子内接触的形成相关。形成接触的残基的人类突变与家族性高胆固醇血症（FH）相关，本研究的目的是确定接触残基对LDLR功能的作用。我们发现，在9个接触残基的突变降低了LDLR支持脂蛋白摄取的能力。出乎意料的是，只有四个突变（W515A，W541A，H562Y和H586Y）损害酸依赖性脂蛋白的释放。其余突变通过减少表面受体数量（H190 Y、K560 W、H562 Y和K582 W）或减少能够结合脂蛋白的表面受体比例（W144 A和W193 A）降低LDLR的脂蛋白结合能力。我们还检查了三个残基，远端的接触，这被预测是必要的LDLR采取酸性构象。在我们测试的三种突变（G293S、F362A和G375S）中，一种突变（F362A）降低脂蛋白摄取。总之，这些数据表明分子内界面在LDLR功能中起着多种作用。
The LDL receptor (LDLR) is an endocytic receptor that plays a major role in the clearance of atherogenic lipoproteins from the circulation. During the endocytic process, the LDLR first binds lipoprotein at the cell surface and then traffics to endosomes, where the receptor releases bound lipoprotein. Release is acid-dependent and correlates with the formation of an intramolecular contact within the receptor. Human mutations at residues that form the contact are associated with familial hypercholesterolemia (FH) and the goal of the present study was to determine the role of contact residues on LDLR function. We show that mutations at nine contact residues reduce the ability of the LDLR to support lipoprotein uptake. Unexpectedly, only four of the mutations (W515A, W541A, H562Y and H586Y) impaired acid-dependent lipoprotein release. The remaining mutations decreased the lipoprotein-binding capacity of the LDLR through either reduction in the number of surface receptors (H190Y, K560W, H562Y and K582W) or reduction in the fraction of surface receptors that were competent to bind lipoprotein (W144A and W193A). We also examined three residues, distal to the contact, which were predicted to be necessary for the LDLR to adopt the acidic conformation. Of the three mutations we tested (G293S, F362A and G375S), one mutation (F362A) reduced lipoprotein uptake. Together, these data suggest that the intramolecular interface plays multiple roles in LDLR function.