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Binding site structure of one LRP/RAP complex - implications for a common ligand/receptor binding motif

Item Type:Article
Title:Binding site structure of one LRP/RAP complex - implications for a common ligand/receptor binding motif
Creators Name:Jensen, G.A. and Andersen, O.M. and Bonvin, A.M.J.J. and Bjerrum-Bohr, I. and Etzerodt, M. and Thogersen, H.C. and O'Shea, C. and Poulsen, F.M. and Kragelund, B.B.
Abstract:The low-density lipoprotein receptor-related protein (LRP) interacts with more than 30 ligands of different sizes and structures that can all be replaced by the receptor-associated protein (RAP). The double module of complement type repeats, CR56, of LRP binds many ligands including all three domains of RAP and alpha(2)-macroglobulin, which promotes the catabolism of the Abeta-peptide implicated in Alzheimer's disease. To understand the receptor-ligand cross-talk, the NMR structure of CR56 has been solved and ligand binding experiments with RAP domain 1 (RAPd1) have been performed. From chemical shift perturbations of both binding partners upon complex formation, a HADDOCK model of the complex between CR56 and RAPd1 has been obtained. The binding residues are similar to a common binding motif suggested from alpha(2)-macroglobulin binding studies and provide evidence for an understanding of their mutual cross-competition pattern. The present structural results convey a simultaneous description of both binding partners of an LRP-ligand complex and open a route to a broader understanding of the binding specificity of the LRP receptor, which may involve a general four-residue receptor-ligand recognition motif common to all LRP ligands. The present result may be beneficial in the design of antagonists of ligand binding to the LDL receptor family, and especially of drugs for treatment of Alzheimer's disease.
Keywords:NMR, HADDOCK, Lipoprotein, Domain, SPR
Source:Journal of Molecular Biology
Page Range:700-716
Date:29 September 2006
Official Publication:https://doi.org/10.1016/j.jmb.2006.07.013
PubMed:View item in PubMed

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