Requirement for Natively Unstructured Regions of Mesoderm Development Candidate 2 in Promoting Low-Density Lipoprotein Receptor-Related Protein 6 Maturation

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.