Background:Signaling by G protein-coupled melanocortin-2 receptors requires MRAP, a transmembrane accessory protein that forms antiparallel homodimers. Results: Mutational analysis of MRAP-MRAP-receptor fusion proteins established that MRAP oriented with an extracellular amino terminus is essential. Conclusion: MRAP acts on the outside of the cell in the ACTH-MRAP-MRAP-receptor signaling complex. Significance: The results provide insight into molecular mechanisms of GPCR accessory proteins.

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