Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding

Yonghe Li, Jianglei Chen, Wenyan Lu, Lynn M. McCormick, Jianjun Wang, Guojun Bu

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Wnt co-receptors LRP5 and LRP6 are two members of the low-density lipoprotein receptor family. Receptor-associated protein is not only a specialized chaperone but also a universal antagonist for members of the low-density lipoprotein receptor family. Here we test whether Mesd, a newly identified chaperone for members of the low-density lipoprotein receptor family, also binds to mature receptors at the cell surface and antagonizes ligand binding. We found that Mesd binds to cell surface LRP5 and LRP6, but not to other members of the low-density lipoprotein receptor family. Scatchard analysis revealed that Mesd binds cell surface LRP6 with high affinity (Kd ∼3.3 nM). Interestingly, the C-terminal region of Mesd, which is absent in sequences from invertebrates, is necessary and sufficient for binding to mature LRP6, and is required for LRP6 folding. We also found that LRP6 is not a constitutively active endocytosis receptor and binding of the receptor-associated protein to LRP6 partially competes for Mesd binding. Finally, we demonstrated that Mesd antagonizes ligand binding to LRP6 at the cell surface. Together our results show that in addition to serving as a folding chaperone, Mesd can function as a receptor antagonist by inhibiting ligand binding to mature LRP6.

Original languageEnglish (US)
Pages (from-to)5305-5314
Number of pages10
JournalJournal of cell science
Volume118
Issue number22
DOIs
StatePublished - Nov 15 2005

Keywords

  • DKK1
  • LDLR family
  • LRP6
  • Mesd
  • RAP
  • Wnt signaling

ASJC Scopus subject areas

  • Cell Biology

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