The melanocortin 2 receptor accessory protein exists as a homodimer and is essential for the function of the melanocortin 2 receptor in the mouse y1 cell line

Cooray, Sadani N.; Almiro Do Vale, Isabel; Leung, Kit-Yi; Webb, Tom R.; Chapple, J. Paul; Egertová, Michaela; Cheetham, Michael E.; Elphick, Maurice R.; Clark, Adrian J. L.

doi:10.1210/en.2007-1463

Cited by 73Receptor Mechanisms and SignalingAdrenal Hormones and DisordersNeuropeptides and Animal Physiology

The melanocortin 2 receptor accessory protein exists as a homodimer and is essential for the function of the melanocortin 2 receptor in the mouse y1 cell line

Cooray, Sadani N., Almiro Do Vale, Isabel, Leung, Kit-Yi, Webb, Tom R., Chapple, J. Paul, Egertová, Michaela, Cheetham, Michael E., Elphick, Maurice R. +1 more·2008·Endocrinology

DOI 10.1210/en.2007-1463

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Abstract

The ACTH receptor [melanocortin 2 receptor (MC2R)] gene produces a functional receptor only when transfected into cells of adrenocortical origin, implying that it may require an adrenal-specific accessory factor. Recently we showed that the MC2R accessory protein (MRAP) is essential for the cell surface expression of the MC2R in such models. Using RNA interference (RNAi) technology, we have further explored the action of MRAP in the functioning of the MC2R in Y1 mouse adrenocortical cells that endogenously express MRAP and MC2R. We created stable cell lines expressing mouse MRAP short hairpin RNA (shRNAs) by transfecting cells with an expression vector containing the MRAP small interfering RNA sequence. The knockdown of MRAP resulted in a reduction in MC2R signaling. The overexpression of a mouse MRAP-Flag construct did not restore the expression of MRAP due to its degradation by the mouse shRNAs. The introduction of human MRAP that is resistant to silencing by mouse MRAP shRNAs resulted in the rescue of the MC2R signaling. MRAP migrates on SDS-PAGE with markedly lower mobility than predicted for a 14.1-kDa protein. Coimmunoprecipitation and mass spectroscopy suggests that MRAP exists as a homodimer that is resistant to dissociation by sodium dodecyl sulfate and reducing agents.

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MRAP is necessary for trafficking and cell surface expression of MC2R, as well as ACTH binding and signal transduction.
“Melanocortin receptor accessory protein is a highly unusual protein in that it naturally exists as an antiparallel homodimer and seems to be necessary for trafficking and cell surface expression of the MC2R, as well as binding of ACTH and hence signal transduction (36, 37).”
From ACTH Antagonists (2016) · cites this paper as [37]

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Authors: Cooray, S. N., Almiro Do Vale, I., Leung, K.-Y., Webb, T. R., Chapple, J. P., Egertová, M., Cheetham, M. E., Elphick, M. R., & Clark, A. J. L.
Affiliations: William Harvey Research Institute (GB)
Centre for Endocrinology (S.N.C., I.A.D.V., T.R.W., J.P.C., A.J.L.C.) William Harvey Research Institute, Barts and the London, London EC1M 6BQ, United Kingdom
School of Biological and Chemical Sciences (I.A.D.V., M.E., M.R.E.), Queen Mary University of London, London E1 1BB, United Kingdom
University College London (GB)
Queen Mary University of London (GB)
Corresponding author: Clark, Adrian J. L.
ORCID: Leung, Kit-Yi
Webb, Tom R.
Chapple, J. Paul
Cheetham, Michael E.
Elphick, Maurice R.
Clark, Adrian J. L.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2007-12-27
Volume: 149
Issue: 4
Pages: 1935-1941
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2007-1463
OpenAlex: W2044669705
Cited by: 73
References: 27
Citations by year: 2025: 4 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 5
FWCI: 3.31
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Leicester Research Archive (University of Leicester) (submittedVersion)
Funders: Queen Mary University of London
Wellcome Trust
Directorate for Biological Sciences
Biotechnology and Biological Sciences Research Council
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, homodimer, ACTH receptor, receptor signaling, RNAi knockdown, shRNA, protein degradation, receptor surface expression
MeSH terms: Adrenal Cortex, Animals, Cells, Cultured, Membrane Proteins, Signal Transduction, Dimerization, Receptor, Melanocortin, Type 2, Mice

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The melanocortin 2 receptor accessory protein exists as a homodimer and is essential for the function of the melanocortin 2 receptor in the mouse y1 cell line

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