Melanocortin 3 receptor has a 5' exon that directs translation of apically localized protein from the second in-frame ATG

Research output: Contribution to journalArticle

Abstract

Melanocortin-3 receptor (MC3R) is a canonical MSH receptor that plays an essential role in energy homeostasis. Variants in MC3R have been implicated in obesity in humans and mice. However, interpretation of the functional consequences of these variants is challenging because the translational start site of MC3R is unclear. Using 5' rapid amplification of cDNA ends, we discovered a novel upstream exon that extends the length of the 5' untranslated region (UTR) in MC3R without changing the open-reading frame. The full-length 5' UTR directs utilization of an evolutionarily conserved second in-frame ATG as the primary translation start site. MC3R synthesized from the second ATG is localized to apical membranes of polarized Madin-Darby canine kidney cells, consistent with its function as a cell surface mediator of melanocortin signaling. Expression of MC3R causes relocalization of melanocortin receptor accessory protein 2, an accessory factor for melanocortin-2 receptor, to the apical membrane, coincident with the location of MC3R. In contrast, protein synthesized from MC3R cDNAs lacking the 5' UTR displayed diffuse cytosolic distribution and has no effect on the distribution of melanocortin receptor accessory protein 2. Our findings demonstrate that a previously unannotated 5' exon directs translation of MC3R protein that localizes to apical membranes of polarized cells. Together, our work provides insight on the structure of human MC3R and reveals a new pathway for regulation of energy metabolism.

Original languageEnglish (US)
Pages (from-to)1547-1557
Number of pages11
JournalMolecular Endocrinology
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2014

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Receptor, Melanocortin, Type 3
Exons
Proteins
5' Untranslated Regions
Melanocortin Receptors
Receptor, Melanocortin, Type 2
Complementary DNA
Melanocortins
Madin Darby Canine Kidney Cells
Membranes
Energy Metabolism
Open Reading Frames
Homeostasis
Obesity
Cell Membrane

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Melanocortin 3 receptor has a 5' exon that directs translation of apically localized protein from the second in-frame ATG",
abstract = "Melanocortin-3 receptor (MC3R) is a canonical MSH receptor that plays an essential role in energy homeostasis. Variants in MC3R have been implicated in obesity in humans and mice. However, interpretation of the functional consequences of these variants is challenging because the translational start site of MC3R is unclear. Using 5' rapid amplification of cDNA ends, we discovered a novel upstream exon that extends the length of the 5' untranslated region (UTR) in MC3R without changing the open-reading frame. The full-length 5' UTR directs utilization of an evolutionarily conserved second in-frame ATG as the primary translation start site. MC3R synthesized from the second ATG is localized to apical membranes of polarized Madin-Darby canine kidney cells, consistent with its function as a cell surface mediator of melanocortin signaling. Expression of MC3R causes relocalization of melanocortin receptor accessory protein 2, an accessory factor for melanocortin-2 receptor, to the apical membrane, coincident with the location of MC3R. In contrast, protein synthesized from MC3R cDNAs lacking the 5' UTR displayed diffuse cytosolic distribution and has no effect on the distribution of melanocortin receptor accessory protein 2. Our findings demonstrate that a previously unannotated 5' exon directs translation of MC3R protein that localizes to apical membranes of polarized cells. Together, our work provides insight on the structure of human MC3R and reveals a new pathway for regulation of energy metabolism.",
author = "Jeenah Park and Neeraj Sharma and Cutting, {Garry R}",
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