Melanocortin 2 receptor accessory protein 2 is a protein that in humans is encoded by the MRAP2 gene. MRAP2 is a transmembrane accessory protein to a family of five receptors called the melanocortin receptors (MC1-5). Human genome sequencing analysis led to the discovery of MRAP2, Human MRAP2 gene is located in chromosome 6q14.3, a different chromosomal location from that of human MRAP which is a paralogy to MRAP2. MRAP2 is thought to be involved in regulating the expression of the melanocortin (MC1-5) and some non-melanocortin receptors such as ghrelin receptor (GHSR-1a), orexin (OX1R) receptor and prokineticin receptor (PKR-1).
MRAP2 was found first in the adrenal gland and the brain. However, the Human protein Atlas/ RNA-seq analysis data of human genome detected MRAP2 in other tissues such as ovary, endometrium, testis, digestive tract, pituitary gland and skin.
The MRAP2 function was found to be associated with regulating appetite and energy expenditure. This is through regulating different receptors involved in the brain circuit regulating those two functions. Such receptors include MC4, MC3, GHSR-1a, PKR-1 and OX1R.
Structure and functional regions
The MRAP2 gene is located in chromosome 6q14.3 and is composed of 4 exons with the first exon containing a non-coding sequence. The translated MRAP2 protein is a 205 amino acids single-pass transmembrane protein. The amino- (N-) terminal and the transmembrane domain were found to show a 40% similarity between MRAP2 and MRAP, while the Carboxyl- (C-) terminal is found to be different between the two proteins.
The different domains of MRAP2 were found to have different functions. The C-terminal was found essential for the inhibition of the activity of certain receptors (OX1R and PKR-1). Different sequences of the N- terminal have two separate function with the 23-33 amino sequence being responsible for the surface expression of OX1R, while the 34-43 sequence was found to have a negative auto-regulatory role over MRAP2 function.
MRAP2 is located both on the cell membrane and also sub-cellularly in the endoplasmic reticulum. The MRAP2 shares a unique feature with MRAP as both were found to show a dual topology orientation. Immunofluorescence imaging and live cell imaging studies showed both the C- terminal and the N-terminal expressed on the cell membrane and in the luminal surface of the endoplasmic reticulum. The Dual orientation feature enables the formation of homodimers (MRAP2/MRAP2) and heterodimer (MRAP2/MRAP). Post-translational processing of MRAP2 protein includes the N-linked glycosylation which plays an important factor in MRAP2 enabling MC2 stimulation by adrenocorticotropic hormone (ACTH).
Phylogenetic studies had located MRAP2 gene in different species such as mammals, chickens, piscine species (tetrapod and zebrafish), bony fish subspecies, sea lamprey and cartilaginous fish. The detection of MRAP2 in the last two species suggested that MRAP2 as an ancestral role by giving rise to MRAP through gene duplication as MRAP was absent in those two species. but this claim was dismissed upon locating MRAP cDNA in elephant sharks.
Cellular activity
The distribution of MRAP2 in the brain within the appetite control and weight control regions revealed its involvement in those two regulatory circuits. MRAP2 was found regulate the expression and response of MC4, and MC3. MC4 role has a well described in appetite control in the brain. MC4 is mediating an anorexic effect in the hypothalamus. MRAP2 was found in high levels in brain regions that is associated with feeding behaviour such as the paraventricular nucleus of the hypothalamus. MRAP2/MC4 double knockout transgenic mice were found morbidly obese. Also, the treatment of MC4/MRAP2 transfected cells with the melanocortin ligand alpha -melanocyte stimulating hormone (α-MSH) generated a response (increased cAMP production). Similar response was seen in MC3/MRAP2 transfected cells which indicate an interaction of MRAP2 with the two anorexic receptors in the brain.