Adrenocorticotropic hormone (ACTH) responses require actions of the melanocortin-2 receptor accessory protein on the extracellular surface of the plasma membrane
Open accessAbstract
The melanocortin-2 (MC2) receptor is a G protein-coupled receptor that mediates responses to ACTH. The MC2 receptor acts in concert with the MC2 receptor accessory protein (MRAP) that is absolutely required for ACTH binding and signaling. MRAP has a single transmembrane domain and forms a highly unusual antiparallel homodimer that is stably associated with MC2 receptors at the plasma membrane. Despite the physiological importance of the interaction between the MC2 receptor and MRAP, there is little understanding of how the accessory protein works. The dual topology of MRAP has made it impossible to determine whether highly conserved and necessary regions of MRAP are required on the intracellular or extracellular face of the plasma membrane. The strategy used here was to fix the orientation of two antiparallel MRAP molecules and then introduce inactivating mutations on one side of the membrane or the other. This was achieved by engineering proteins containing tandem copies of MRAP fused to the amino terminus of the MC2 receptor. The data firmly establish that only the extracellular amino terminus (Nout) copy of MRAP, oriented with critical segments on the extracellular side of the membrane, is essential. The transmembrane domain of MRAP is also required in only the Nout orientation. Finally, activity of MRAP-MRAP-MC2-receptor fusion proteins with inactivating mutations in either MRAP or the receptor was rescued by co-expression of free wild-type MRAP or free wild-type receptor. These results show that the basic MRAP-MRAP-receptor signaling unit forms higher order complexes and that these multimers signal.
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Malik et al. have shown that the N-terminal region of MRAP is required on the extracellular surface of the cell for ACTH binding.
“It is notable that Malik et al. have shown that it is the N-terminal region of the MRAP molecule that is required on the extracellular surface of the cell for ACTH binding (48).”
From ACTH Antagonists (2016) · cites this paper as [48]
In “MRAP Regulation of MC2 Receptor Signaling” (page unavailable), mutations in the extracellular N-terminal copy of MRAP greatly reduced ACTH responses, while the same mutations in the intracellular copy had little effect. The authors say the extracellular regions are required for either ACTH binding or ACTH-dependent conformational changes; this experiment does not establish binding specifically. (LLM, conf=0.86)
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- Authors
- Malik, S., Dolan, T. M., Maben, Z. J., & Hinkle, P. M.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Hinkle, Patricia M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 290
- Issue
- 46
- Pages
- 27972-27985
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4646036
- OpenAlex
- W2177303033
- Cited by
- 41
- References
- 39
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 6 · 2016: 8
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK19974, DK67214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- melanocortin 2 receptor, MRAP, ACTH, G protein-coupled receptor signaling, membrane orientation, transmembrane domain, fusion protein, ACTH signaling
- MeSH terms
- Adrenocorticotropic Hormone, Amino Acid Sequence, Cell Membrane, Humans, Membrane Proteins, Molecular Sequence Data, Mutation, Recombinant Fusion Proteins, Protein Engineering, Signal Transduction, Protein Structure, Tertiary, Protein Multimerization, HEK293 Cells
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