The Role of α2Macroglobulin Receptor Associated Protein as a Chaperone for Multifunctional Receptors

Abstract

The α2macroglobulin receptor associated protein (RAP) is a 39 kDa large glycoprotein of 323 amino acid residues, which binds to members of the low density lipoprotein receptor (LDLR) family. These receptors are large multifunctional endocytic receptors capable of binding and internalizing many different ligands, such as lipoproteins and complexes of proteinases and their inhibitors. While RAP is able to inhibit binding of all currently known extracellular ligands of these receptors in in vitro assays, the protein is an intracellular ER- and Golgi-resident protein which serves a function as a molecular chaperone for LDLR family members. The intracellular binding of RAP to these receptors assists their folding and prevents premature binding of other ligands in the endocytic pathway. Here we describe the role of RAP as a molecular chaperone for LDLR family members, as well as the interaction between RAP and two recently discovered non-family member receptors, gp95/sortilin and sorLA-1. Based on ligand competition analysis and the recently solved three-dimensional structure of the N-terminal domain of RAP, a model of RAP domain 1/receptor interaction is proposed.