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Melanocortin 2 receptor accessory protein

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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MRAP
Identifiers
AliasesMRAP, B27, C21orf61, FALP, FGD2, GCCD2, melanocortin 2 receptor accessory protein
External IDsOMIM: 609196; MGI: 1924287; HomoloGene: 12669; GeneCards: MRAP; OMA:MRAP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

56246

77037

Ensembl

ENSG00000170262

ENSMUSG00000039956

UniProt

Q8TCY5

Q9D159

RefSeq (mRNA)

NM_001285394
NM_178817
NM_206898
NM_001379228

NM_029844

RefSeq (protein)

NP_001272323
NP_848932
NP_996781
NP_001366157

NP_084120

Location (UCSC)Chr 21: 32.29 – 32.31 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Melanocortin 2 receptor accessory protein is a transmembrane accessory protein that in humans is encoded by the MRAP gene[4] located in chromosome 21q22.11.[5] Alternate splicing of the MRAP mRNA generates two functionally isoforms MRAP-α and MRAP-β.[6]

MRAP is an accessory protein to a family of five receptors called the melanocortin receptors (MC1-5). It was previously known as fat tissue-specific low molecular weight protein (Falp). MRAP was thought to be involved in adipocytes differentiation.[6] MRAP assists in the transport of the melanocortin 2 receptor to the cell membrane from the endoplasmic reticulum and assist in the generation of cAMP by the activated receptor. MRAP is also considered essential for the trafficking of MC2 to the cell surface and facilitate the MC2 response to adrenocorticotropic hormone (ACTH) in the adrenal gland leading to stimulation of glucocorticoid synthesis.

Human MRAP is found mainly in the adrenal gland and adipose tissue. It was also located in the brain, heart, ovary, testes, and breast.[5] Genetic variants of MRAP are linked to an autosomal recessive condition called Familial Glucocorticoid Deficiency type 2 (FGD-2).[5]

Structure and functional domains

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The cytogenetic location of MRAP gene is 21q22.11 and is composed of 6 exons that encodes a single-pass transmembrane protein. The protein is made of three domains: a transmembrane domain that is responsible for the attachment of the MRAP molecule in the cell membrane and facilitates the interaction with the receptor. The second domain assists MRAP expression on the cell membrane as well as the expression of MC2. The third and final domain that is near the amino- (N-) terminal enables the homodimerization of MRAP molecules.[7] The N-terminal and the transmembrane domains are highly conserved between species. In contrast, the carboxyl-(C-) terminal is found to be diverging between the MRAP isoforms and also between different species. That said, the whole genome of human MRAP shares lower similarity with mouse Mrap, and that is mainly in the N-terminal and transmembrane domain.

The alternate splicing of the MRAP mRNA generates 4 isoforms: two functional isoforms which are MRAP-α (173 amino acids); MRAP-β (102 amino acids); non-functional isoforms, isoform 3 (113 amino acids); and isoform 4 (172 amino acids).[6][5] MRAP, and its ortholog MRAP2, is the dual topology where either the C- or the N- terminal is oriented extracellularly. This dual topology feature was revealed using epitope immunoprecipitation and live cell imaging studies.[8] MRAP is partially glycosylated and this is dependent on the N-terminal being facing the luminal surface of the endoplasmic reticulum.[9] This unique feature enables MRAP to form an antiparallel homodimer that is essential for the MRAP interaction with the melanocortin receptors.[8]

The expression of MRAP was found to be regulated by ACTH as well as lipopolysaccharides [10][11][12] and, in rats, is affected by diurnal variation.[13] Phylogenetic studies revealed the existence of MRAP orthologs in different piscine species such as zebrafish and tetrapod and has also been detected in mammals and chicken.[14] MRAP is thought to be originated as a result of R2 genome duplication event.[15]

Cellular activity

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MRAP was found to mainly regulate the surface expression and signalling of MC2. Cell surface ELISA and Immunofluorescence studies showed the co-expression of MC2/MRAP in endoplasmic reticulum (ER) and also on the cell membrane, which indicates that MC2 needs MRAP to reach the cell membrane.[5] In addition to cell trafficking, in vitro studies conducted on HEK293 cell[16] revealed that MRAP enhances MC2 response to ACTH stimulation and the effect of MRAP-β was more pronounced than that of MRAP-α.[10] The activated MC2 activates cAMP production which, in turn, stimulates the protein kinase A (PKA) pathway leading to glucocorticoid synthesis in the adrenal gland.[5] In fat cells, where MC2 is expressed, MRAP was found to facilitate MC2 activated lipolysis and therefore regulating energy expenditure.[17] The transmembrane domain of MRAP mediates MRAP/MC2 interaction, and that suggests an interaction with the transmembrane domain of one of the seven domains of MC2.[7] Once the interaction is established, MRAP uses its tyrosine-rich region to escort MC2 to the cell membrane. However, MRAP needs to be in the antiparallel homodimer status.[7][12] The MC2/MRAP complex expression on the cell membrane culminates in MRAP assisting MC2 to respond to ACTH stimulation, and that is through the same MRAP tyrosine rich area mentioned earlier.[7]

In addition to regulating MC2 surface expression and signalling, MRAP was found to modulate the function of the other melanocortin receptors. Immunoprecipitation assays reported the interaction of MRAP with MC4and MC5 and had no effect on the surface expression of MC1 and MC3. Unlike MC2, MRAP is not essential for these receptors as they were located on the cell surface in the absence of MRAP1.[18] The interaction between MCs and MRAP was found to reduce the former response to the melanocortin synthetic ligand NDP-MSH [13]

Familial glucocorticoid deficiency (FGD)

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The familial glucocorticoid deficiency occurs as a result of poor adrenal response to ACTH stimulation which leads to glucocorticoid deficiency. The mutations in the MRAP gene caused the congenital disorder familial glucocorticoid deficiency type 2 (FGD-2). FGD-2 is an autosomal recessive disease with early childhood onset of recurrent infections, hypoglycaemia, skin hyperpigmentation, and failure to thrive due to low glucocorticoids levels. If left untreated, it could be fatal. MRAP mutations were found to disable the movement of MC2 to the cell surface of adrenal gland cells; this would make MC2 irresponsive to ACTH stimulation causing a deficiency in glucocorticoids production.[5] The mutations in the MRAP gene were found to be mostly homozygous nonsense or splice-site mutations that caused the truncation of MRAP protein.[12][19] Few FGD-2 cases were reported to have homozygous missense MRAP gene mutations that led to replacing tyrosine with asparagine at position 59 or the substitution of valine with alanine at position 26. These missense mutations cause a milder form of the disease and a later onset.[12][20] The mutations in the MRAP gene sequence that cause FGD-2 are considered rare compared to the effect of chronic corticosteroid treatment that leads to adrenal insufficiency disrupting the MC2/MRAP stimulation by ACTH.

The adrenal cortex is made of three zones: zona glomerulosa, zona fasciculata and zona reticularis. The main zone that expresses MC2 and MRAP is the zona fasciculata.[21] Both proteins are also found in the undifferentiated region of the adrenal gland, where there is a small population of adrenal stem cells [22] The use of MRAP knockout transgenic mice revealed under-developed adrenal gland with loss of the adrenal zonation,[23] which indicates another mechanism for FGD-2.

There is still no profound evidence of the involvement of MRAP in disorders beyond the adrenal gland. However, MC2 lipolytic activity was disturbed in the adipose tissue in the presence of mutated MRAP.[17] Nevertheless, the MRAP mutations that caused FGD-2 did not seem to affect fat metabolism in the affected patients. This might indicate a compensatory mechanism to the loss of MRAP function in adipocytes.

The presence of MRAP in regions with no or low MC2 levels might indicate a role of MRAP beyond MC2 and the other melanocortin receptors. Ongoing studies using transgenic mice and array genotyping could give insight into the physiological processes involving MRAP.

Notes

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000170262 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Entrez Gene: Melanocortin 2 receptor accessory protein".
  5. ^ a b c d e f g Metherell LA, Chapple JP, Cooray S, David A, Becker C, Rüschendorf F, et al. (February 2005). "Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2". Nature Genetics. 37 (2): 166–70. doi:10.1038/ng1501. PMID 15654338. S2CID 19104175.
  6. ^ a b c Xu A, Choi KL, Wang Y, Permana PA, Xu LY, Bogardus C, Cooper GJ (May 2002). "Identification of novel putative membrane proteins selectively expressed during adipose conversion of 3T3-L1 cells". Biochemical and Biophysical Research Communications. 293 (4): 1161–7. doi:10.1016/S0006-291X(02)00354-6. PMID 12054497.
  7. ^ a b c d Webb TR, Chan L, Cooray SN, Cheetham ME, Chapple JP, Clark AJ (February 2009). "Distinct melanocortin 2 receptor accessory protein domains are required for melanocortin 2 receptor interaction and promotion of receptor trafficking". Endocrinology. 150 (2): 720–6. doi:10.1210/en.2008-0941. PMC 6602883. PMID 18818285.
  8. ^ a b Sebag JA, Hinkle PM (December 2007). "Melanocortin-2 receptor accessory protein MRAP forms antiparallel homodimers". Proceedings of the National Academy of Sciences of the United States of America. 104 (51): 20244–9. Bibcode:2007PNAS..10420244S. doi:10.1073/pnas.0708916105. PMC 2154416. PMID 18077336.
  9. ^ Sebag JA, Hinkle PM (August 2009). "Opposite effects of the melanocortin-2 (MC2) receptor accessory protein MRAP on MC2 and MC5 receptor dimerization and trafficking". The Journal of Biological Chemistry. 284 (34): 22641–8. doi:10.1074/jbc.M109.022400. PMC 2755671. PMID 19535343.
  10. ^ a b Liu Y, Smith LI, Huang V, Poon V, Coello A, Olah M, et al. (May 2013). "Transcriptional regulation of episodic glucocorticoid secretion". Molecular and Cellular Endocrinology. 371 (1–2): 62–70. doi:10.1016/j.mce.2012.10.011. PMC 3582781. PMID 23138111.
  11. ^ Gibbison B, Spiga F, Walker JJ, Russell GM, Stevenson K, Kershaw Y, et al. (April 2015). "Dynamic pituitary-adrenal interactions in response to cardiac surgery". Critical Care Medicine. 43 (4): 791–800. doi:10.1097/CCM.0000000000000773. PMC 4359905. PMID 25517478.
  12. ^ a b c d Berruien, Nasrin N. A.; Smith, Caroline L. (2020-10-05). "Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology". Gene. 757: 144949. doi:10.1016/j.gene.2020.144949. ISSN 0378-1119. PMC 8459444. PMID 32679290.
  13. ^ a b Spiga F, Zhao Z, Lightman SL (March 2020). "Prolonged treatment with the synthetic glucocorticoid methylprednisolone affects adrenal steroidogenic function and response to inflammatory stress in the rat". Brain, Behavior, and Immunity. 87: 703–714. doi:10.1016/j.bbi.2020.03.001. PMC 7327516. PMID 32156515.
  14. ^ Valsalan R, Krishnan A, Almén MS, Fredriksson R, Schiöth HB (July 2013). "Early vertebrate origin of melanocortin 2 receptor accessory proteins (MRAPs)". General and Comparative Endocrinology. 188: 123–32. doi:10.1016/j.ygcen.2013.01.004. PMID 23370304.
  15. ^ Ohno S, Wolf U, Atkin NB (2009-09-02). "Evolution from fish to mammals by gene duplication". Hereditas. 59 (1): 169–87. doi:10.1111/j.1601-5223.1968.tb02169.x. PMID 5662632.
  16. ^ Roy S, Rached M, Gallo-Payet N (July 2007). "Differential regulation of the human adrenocorticotropin receptor [melanocortin-2 receptor (MC2R)] by human MC2R accessory protein isoforms alpha and beta in isogenic human embryonic kidney 293 cells". Molecular Endocrinology. 21 (7): 1656–69. doi:10.1210/me.2007-0041. PMID 17456795.
  17. ^ a b Zhang X, Saarinen AM, Campbell LE, De Filippis EA, Liu J (February 2018). "Regulation of Lipolytic Response and Energy Balance by Melanocortin 2 Receptor Accessory Protein (MRAP) in Adipocytes". Diabetes. 67 (2): 222–234. doi:10.2337/db17-0862. PMC 5780064. PMID 29217655.
  18. ^ Chan LF, Webb TR, Chung TT, Meimaridou E, Cooray SN, Guasti L, et al. (April 2009). "MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family". Proceedings of the National Academy of Sciences of the United States of America. 106 (15): 6146–51. Bibcode:2009PNAS..106.6146C. doi:10.1073/pnas.0809918106. PMC 2661846. PMID 19329486.
  19. ^ Jain V, Metherell LA, David A, Sharma R, Sharma PK, Clark AJ, Chan LF (December 2011). "Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein". European Journal of Endocrinology. 165 (6): 987–91. doi:10.1530/EJE-11-0581. PMC 3214758. PMID 21951701.
  20. ^ Hughes CR, Chung TT, Habeb AM, Kelestimur F, Clark AJ, Metherell LA (July 2010). "Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2". The Journal of Clinical Endocrinology and Metabolism. 95 (7): 3497–501. doi:10.1210/jc.2009-2731. PMID 20427498.
  21. ^ Manna PR, Eubank DW, Lalli E, Sassone-Corsi P, Stocco DM (June 2003). "Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1". Journal of Molecular Endocrinology. 30 (3): 381–97. doi:10.1677/jme.0.0300381. PMID 12790807.
  22. ^ Walczak EM, Hammer GD (January 2015). "Regulation of the adrenocortical stem cell niche: implications for disease". Nature Reviews. Endocrinology. 11 (1): 14–28. doi:10.1038/nrendo.2014.166. PMC 4648246. PMID 25287283.
  23. ^ Novoselova TV, Hussain M, King PJ, Guasti L, Metherell LA, Charalambous M, et al. (June 2018). "MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation". FASEB Journal. 32 (11): 6186–6196. doi:10.1096/fj.201701274RR. PMC 6181639. PMID 29879378.
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