Evaluating the Interaction Between the Human Melanocortin-2 Receptor and the Accessory Protein, Mrap1: Chimeric Receptor and Alanine Substitution Studies on Transmembrane Domain 4, Extracellular Loop 2, and Transmembrane Domain 5

<p>The melanocortin-2 receptor (MC2R) is the most complex due to its trafficking and ligand selectivity requirements for proper activation. The MC2R requires the melanocortin receptor accessory protein-1 (MRAP1) for proper trafficking and activation of the receptor by the melanocortin hormone, ACTH. MRAP1 is a single transmembrane-spanning domain protein that creates a homodimer with another MRAP1 protein. Furthermore, MRAP2 creates a heterodimer with the MC2R. Previous studies have shown that the MRAP1 protein contains an activation motif required for activation of MC2R and this activation motif located on the extracellular space side of the plasma membrane of the cell. The objective of this dissertation was to analyze potential contact sites between the extracellular space side activation motif of MRAP1 with the extracellular domains of the MC2R—the N-terminal, extracellular loop 1, extracellular loop 2, and extracellular loop 3. This analysis utilized a chimeric protein paradigm as well as alanine substitution experiments to observe potential contact sites between MRAP1 and the MC2R. By using these approaches, important residues required for trafficking or activation were identified in transmembrane 4, extracellular loop 2, and transmembrane 5 domains for MC2R. These results propose a revised mechanism for MC2R activation. Finally, the revised model suggests evolutionary implications for vertebrate MC2R activation.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Year dc:date.available

2018

Author dc:creator

• Davis, Perry Victoria

Contributors dc:contributor

• Robert M. Dores, Ph.D.
• Phil Danielson
• Joseph Angleson
• James Fogleman

• Alanine substitution
• Chimeric receptor
• MC2R
• Melanocortin-2 receptor
• Melanocortin receptor accessory protein 1
• MRAP1
• Biochemistry
• Cell Biology

Statement dc:rights

• <p>Copyright is held by the author. User is responsible for all copyright compliance.</p>

Language dc:language

en

Repository record dc:identifier

https://digitalcommons.du.edu/etd/1530

OAI identifier oai:identifier

oai:digitalcommons.du.edu:etd-2530