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

• Published in: Molecular and cellular endocrinology 2009-03, Vol.300 (1-2), p.25-31
• Main Authors: Hinkle, Patricia M., Sebag, Julien A.
• Format: Article
• Language: English
• Subjects: ACTH; Adrenocorticotropic Hormone - metabolism; Animals; cAMP; Cell Line; Dual topology; GPCR; Humans; Melanocortin receptor; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; MRAP; Protein Structure, Quaternary
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2008.10.041

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.