The Roles of Receptor-associated Protein (RAP) As a Molecular Chaperone for Members of the LDL Receptor Family

Members of the LDL receptor family mediate endocytosis and signal transduction of many extracellular ligands which participate in lipoprotein metabolism, protease regulation, embryonic development, and the pathogenesis of disease (e.g., Alzheimer's disease). Structurally, these receptors share common motifs and modules that are highlighted with clusters of cysteine-rich ligand-binding repeats. Perhaps, the most significant feature that is shared by members of the LDL receptor family is the ability of a 39-kDa receptor-associated protein (RAP) to universally inhibit ligand interaction with these receptors. Under physiological conditions, RAP serves as a molecular chaperone/escort protein for these receptors to prevent premature interaction of ligands with the receptors and thereby ensures their safe passage through the secretory pathway. In addition, RAP promotes the proper folding of these receptors, a function that is likely independent from its ability to inhibit ligand binding. The molecular mechanisms underlying these functions of RAP, as well as the molecular determinants that contribute to RAP-receptor interaction will be discussed in this review. Elucidation of these mechanisms should help to clarify how a specialized chaperone promotes the biogenesis of LDL receptor family members, and may provide insights into how the expression and function of these receptors can be regulated via the expression of RAP under pathological states.