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J. Biol. Chem., Vol. 276, Issue 31, 29338-29346, August 3, 2001

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High Affinity Binding of Receptor-associated Protein to Heparin and Low Density Lipoprotein Receptor-related Protein Requires Similar Basic Amino Acid Sequence Motifs^*

Lora Melman, Zhao-feng Cao^§, Stephanie Rennke, Maria Paz Marzolo^¶, Mark R. Wardell^§, and Guojun Bu^**

From the  Departments of Pediatrics and Cell Biology and Physiology and ^§ Biochemistry and Molecular Biophysics and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶ Department of Biology, University of Chile, Santiago, Chile

The 39-kDa receptor-associated protein (RAP) is a specialized chaperone for members of the low density lipoprotein receptor gene family, which also binds heparin. Previous studies have identified a triplicate repeat sequence within RAP that appears to exhibit differential functions. Here we generated a series of truncated and site-directed RAP mutants in order to define the sites within RAP that are important for interacting with heparin and low density lipoprotein receptor-related protein (LRP). We found that high affinity binding of RAP to heparin is mediated by the carboxyl-terminal repeat of RAP, whereas both the carboxyl-terminal repeat and a combination of amino and central repeats exhibit high affinity binding to LRP. Several motifs were found to mediate the binding of RAP to heparin, and each contained a cluster of basic amino acids; among them, an intact R²⁸²VSR²⁸⁵SR²⁸⁷EK²⁸⁹ motif is required for high affinity binding of RAP to heparin, whereas two other motifs, R²⁰³LR²⁰⁵R²⁰⁶ and R³¹⁴ISR³¹⁷AR³¹⁹, also contribute to this interaction. We also found that intact motifs of both R²⁰³LR²⁰⁵R²⁰⁶ and R²⁸²VSR²⁸⁵SR²⁸⁷EK²⁸⁹ are required for high affinity binding of RAP to LRP, with the third motif, R³¹⁴ISR³¹⁷AR³¹⁹, contributing little to RAP-LRP interaction. We conclude that electrostatic interactions likely contribute significantly in the binding of RAP to both heparin and LRP and that high affinity interaction with both heparin and LRP appears to require mostly overlapping sequence motifs within RAP.

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