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J. Biol. Chem., Vol. 281, Issue 45, 34189-34196, November 10, 2006

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Three Complement-like Repeats Compose the Complete ₂-Macroglobulin Binding Site in the Second Ligand Binding Cluster of the Low Density Lipoprotein Receptor-related Protein^*

From the Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607

Given the importance of the low density lipoprotein receptor-related protein (LRP) as an essential endocytosis and signaling receptor for many protein ligands, and of ₂-macroglobulin (₂M)-proteinase complexes as one such set of ligands, an understanding of the specificity of their interaction with LRP is an important goal. A starting point is the known role of the 138-residue receptor binding domain (RBD) in binding to LRP. Previous studies have localized high affinity ₂M binding to the eight complement repeat (CR)-containing cluster 2 of LRP. In the present study we have identified the minimum CR domains that constitute the full binding site for RBD and, hence, for ₂M on LRP. We report on the ability of the triple construct of CR3-4-5 to bind RBD with an affinity (K_d = 130 nM) the same as for isolated RBD to intact LRP. This K_d is 30-fold smaller than for RBD to CR5-6-7, demonstrating the specificity of the interaction with CR3-4-5. Binding requires previously identified critical lysine residues but is almost pH-independent within the range of pH values encountered between extracellular and internal compartments, consistent with an earlier proposed model of intracellular ligand displacement by intramolecular YWTD domains. The present findings suggest a model to explain the ability of LRP to bind a wide range of structurally unrelated ligands in which a nonspecific ligand interaction with the acidic region present in most CR domains is augmented by interactions with other CR surface residues that are unique to a particular CR cluster.

Received for publication, May 8, 2006 , and in revised form, September 12, 2006.

^* The work was supported by National Institutes of Health Grant GM54414. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, UIC, 900 S Ashland Ave., MC 669, Chicago, IL 60607. Tel.: 312-996-5534; Fax: 312-413-0353; E-mail: pgettins{at}uic.edu.

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