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Distinct Melanocortin 2 Receptor Accessory Protein Domains Are Required for Melanocortin 2 Receptor Interaction and Promotion of Receptor Trafficking

Centre for Endocrinology (T.R.W., L.C., S.N.C., J.P.C., A.J.L.C.), William Harvey Research Institute, Barts and the London, London EC1M 6BQ, United Kingdom; and Division of Molecular and Cellular Neuroscience (M.E.C.), University College of London Institute of Ophthalmology, London EC1V 9EL, United Kingdom

Address all correspondence and requests for reprints to: Adrian J. L. Clark, Centre for Endocrinology (T.R.W., L.C., S.N.C., J.P.C., A.J.L.C.), William Harvey Research Institute, Barts and the London, London EC1M 6BQ, United Kingdom. E-mail: a.j.clark{at}qmul.ac.uk.

Melanocortin 2 receptor (MC2R) is the receptor for the pituitary hormone ACTH. When activated, MC2R stimulates cAMP production and adrenal steroidogenesis. The functional expression of the receptor requires melanocortin 2 receptor accessory protein (MRAP), a single-transmembrane domain protein involved in the trafficking of MC2R from the endoplasmic reticulum to the cell surface. Mutations in both MC2R and MRAP cause the inherited disease familial glucocorticoid deficiency. At present, little is known regarding the mechanism of MRAP in MC2R functional expression. Here we report the characterization of MRAP in the trafficking of MC2R to the cell surface and the formation of a functional receptor. We identify the transmembrane domain of MRAP as the MC2R interaction domain and a conserved N-terminal tyrosine-rich domain of MRAP that is required for trafficking MC2R to the cell surface.

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