Koduri Vidyasagar, Blacklow Stephen C
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochemistry. 2007 Jun 5;46(22):6570-7. doi: 10.1021/bi700049g. Epub 2007 May 9.
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.
低密度脂蛋白受体家族（LRP）的蛋白质是复杂的、多模块的I型跨膜受体。这些蛋白质的有效成熟依赖于一种内质网驻留蛋白，在哺乳动物中称为中胚层发育候选蛋白2（MESD），在果蝇中称为Boca。我们在此表明，MESD包含一个中央折叠结构域，两侧是促进LRP6成熟所需的天然无结构区域。全长人MESD的强制表达促进了源自LRP6的可溶性小受体的分泌，这些小受体包含一个或两个β-螺旋桨-表皮生长因子结构域对。相反，siRNA介导的人MESD表达敲低会阻断天然LRP6小受体的分泌，并显著降低全长LRP6的细胞表面表达水平。只有通过同时递送包含大部分或所有无结构N端和C端的抗siRNA形式的小鼠MESD才能挽救细胞表面表达，这表明MESD的柔性部分在其促进LRP成熟的功能中发挥作用。
