QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 1 November 2005
doi: 10.1242/jcs.02651

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.02651v1 118/22/5305    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Y. Articles by Bu, G. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by Bu, G.

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

Yonghe Li^1,*,, Jianglei Chen², Wenyan Lu¹, Lynn M. McCormick¹, Jianjun Wang² and Guojun Bu^1,3

¹ Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
² Department of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine, 224 Neckers Hall, Carbondale, IL 62901, USA
³ Departments of Cell Biology and Physiology, St Louis Children's Hospital, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA

Author for correspondence (e-mail: y.li{at}sri.org)

Accepted 17 August 2005

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 (K_d 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.

Key words: LRP6, LDLR family, Wnt signaling, Mesd, RAP, DKK1

This article has been cited by other articles:

				W. Liu, S. Mani, N. R. Davis, N. Sarrafzadegan, P. B. Kavathas, and A. Mani Mutation in EGFP Domain of LDL Receptor-Related Protein 6 Impairs Cellular LDL Clearance Circ. Res., November 21, 2008; 103(11): 1280 - 1288. [Abstract] [Full Text] [PDF]

				C. Hassler, C.-M. Cruciat, Y.-L. Huang, S. Kuriyama, R. Mayor, and C. Niehrs Kremen is required for neural crest induction in Xenopus and promotes LRP6-mediated Wnt signaling Development, December 1, 2007; 134(23): 4255 - 4263. [Abstract] [Full Text] [PDF]