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J. Biol. Chem., Vol. 277, Issue 15, 13338-13345, April 12, 2002

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Distinct Binding Sites in the Structure of ₂-Macroglobulin Mediate the Interaction with -Amyloid Peptide and Growth Factors^*

Joseph M. Mettenburg, Donna J. Webb^§, and Steven L. Gonias^¶

From the Departments of  Biochemistry and Molecular Genetics, ^§ Cell Biology, and ^¶ Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908

₂-Macroglobulin (₂M) and its receptor, low density lipoprotein receptor-related protein (LRP), function together to facilitate the cellular uptake and degradation of -amyloid peptide (A). In this study, we demonstrate that A binds selectively to ₂M that has been induced to undergo conformational change by reaction with methylamine. Denatured ₂M subunits, which were immobilized on polyvinylidene difluoride membranes, bound A, suggesting that ₂M tertiary and quaternary structure are not necessary. To determine whether a specific sequence in ₂M is responsible for A binding, we prepared and analyzed defined ₂M fragments and glutathione S-transferase-₂M peptide fusion proteins. A single sequence, centered at amino acids (aa) 1314-1365, was identified as the only major A-binding site. Importantly, A did not bind to the previously characterized growth factor-binding site (aa 718-734). Although the A binding sequence is adjacent to the binding site for LRP, the results of experiments with mutated fusion proteins indicate that the two sites are distinct. Furthermore, a saturating concentration of A did not inhibit LRP-mediated clearance of ₂M-MA in mice. Using various methods, we determined that the K_D for the interaction of A with its binding site in the individual ₂M subunit is 0.7-2.4 µM. The capacity of ₂M to bind A and deliver it to LRP may be greater than that predicted by the K_D, because each ₂M subunit may bind A and the bound A may multimerize. These studies suggest a model in which ₂M has three protein interaction sites with distinct specificities, mediating the interaction with A, growth factors, and LRP.

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