Structure and function of the melanocortin2 receptor accessory protein (MRAP)

The melanocortin2 (MC2), or ACTH receptor, requires MC2 receptor accessory protein (MRAP) for function, and individuals lacking MRAP are ACTH-resistant and glucocorticoid-deficient. MRAP facilitates trafficking of the MC2 receptor to the plasma membrane and is absolutely required for ACTH binding and stimulation of CAMP. MRAP, which contains a single transmembrane domain, has a unique structure, an antiparallel homodimer. It can be isolated from the plasma membrane in a complex with the MC2 receptor. A short sequence just aminoterminal to the transmembrane domain of MRAP is essential for dual topology, while the transmembrane region is not; both are necessary for function. Deletion or alanine-substitution of other aminoterminal regions yields MRAP mutants that promote surface expression of the MC2 receptor but not receptor signaling, These results identify two distinct actions of MRAP: to permit trafficking of the MC2 receptor, and to allow surface receptor binding and signaling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.