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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.
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Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

机译：来自低密度脂蛋白受体的富含半胱氨酸的重复序列的三维结构。

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摘要

The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations in this molecule are associated with familial hypercholesterolemia, a condition which leads to an elevated plasma cholesterol concentration and accelerated atherosclerosis. The N-terminal segment of the LDL receptor contains a heptad of cysteine-rich repeats that bind the lipoproteins. Similar repeats are present in related receptors, including the very low-density lipoprotein receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor, and in proteins which are functionally unrelated, such as the C9 component of complement. The first repeat of the human LDL receptor has been expressed in Escherichia coli as a glutathione S-transferase fusion protein, and the cleaved and purified receptor module has been shown to fold to a single, fully oxidized form that is recognized by the monoclonal antibody IgG-C7 in the presence of calcium ions. The three-dimensional structure of this module has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns. Many of the side chains of the acidic residues, including the highly conserved Ser-Asp-Glu triad, are clustered on one face of the module. To our knowledge, this structure has not previously been described in any other protein and may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins. Calcium ions had only minor effects on the CD spectrum and no effect on the 1H NMR spectrum of the repeat, suggesting that they induce no significant conformational change.
机译：低密度脂蛋白（LDL）受体在哺乳动物胆固醇代谢中起着核心作用，从血浆中清除载有载脂蛋白E和B-100的脂蛋白。该分子的突变与家族性高胆固醇血症有关，该病症导致血浆胆固醇浓度升高和动脉粥样硬化加速。 LDL受体的N末端片段包含结合脂蛋白的富含半胱氨酸重复序列的七肽。类似的重复序列存在于相关的受体中，包括非常低密度的脂蛋白受体和与LDL受体相关的蛋白/α2-巨球蛋白受体，以及在功能上不相关的蛋白质（例如补体的C9成分）中。人类LDL受体的第一个重复序列已在大肠杆菌中以谷胱甘肽S-转移酶融合蛋白的形式表达，并且已裂解和纯化的受体模块已显示折叠成单一的完全氧化的形式，可被单克隆抗体IgG识别-C7在钙离子存在下。该模块的三维结构已通过二维NMR光谱法确定，并显示由β-发夹结构和一系列β转角组成。酸性残基的许多侧链，包括高度保守的Ser-Asp-Glu三联体，都聚集在模块的一个面上。据我们所知，这种结构以前没有在任何其他蛋白质中描述过，可能代表LDL受体中其他模块以及几种其他蛋白质的同源结构域的结构范例。钙离子对CD谱图的影响很小，对重复序列的1H NMR谱图没有影响，表明钙离子不会引起明显的构象变化。

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