Requirement for natively unstructured regions of mesoderm development candidate 2 in promoting low-density lipoprotein receptor-related protein 6 maturation
Requirement for natively unstructured regions of mesoderm development candidate 2 in promoting low-density lipoprotein receptor-related protein 6 maturation
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DOI：
10.1021/bi700049g
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发表时间：
2007-06-05
期刊：
影响因子：
2.9
通讯作者：
Blacklow, Stephen C.
中科院分区：
文献类型：
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作者：
Koduri, Vidyasagar;Blacklow, Stephen C.
低密度脂蛋白受体家族(LRPs)的蛋白质是复杂的、多模块的I型跨膜受体。这些蛋白质的生产性成熟依赖于一种驻留在ER上的蛋白质，在哺乳动物中称为中胚层发育候选2(MESD)，在果蝇中依赖于BocA。我们在这里表明，MESD包含一个中央折叠结构域，两侧是促进LRP6成熟所需的天然非结构化区域。全长人MESD的增强表达促进了来自LRP6的可溶性微型受体的分泌，LRP6含有一个或两个β-螺旋桨-EGF结构域对。相反，siRNA介导的人MESD表达下调阻止了天然LRP6微型受体的分泌，并显著降低了全长LRP6在细胞表面的表达水平。只有同时传递含有大部分或全部非结构N-末端和C-末端的小鼠MESD的siRNA抗性形式，才能挽救细胞表面的表达，暗示MESD的灵活部分具有促进LRP成熟的功能。
Proteins of the low-density lipoprotein receptor family (LRPs) are complex, multimodular type I transmembrane receptors. Productive maturation of these proteins relies on an ER-resident protein called mesoderm development candidate 2 (MESD) in mammals and Boca in Drosophila. We show here that MESD contains a central folded domain flanked by natively unstructured regions required to facilitate maturation of LRP6. Enforced expression of full-length human MESD promotes the secretion of soluble minireceptors derived from LRP6 that contain either one or two beta-propeller-EGF domain pairs. Conversely, siRNA-mediated knockdown of human MESD expression blocks secretion of native LRP6 minireceptors and dramatically reduces the level of cell-surface expression of full-length LRP6. Cell-surface expression is only rescued by simultaneous delivery of siRNA-resistant forms of mouse MESD that contain most or all of the unstructured N- and C-termini, implicating the flexible parts of MESD in its function of promoting LRP maturation.