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<p>The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor – melanocortin-receptor accessory protein 2&#xa0;–&#xa0;Gα<sub>s</sub> complex suggests interaction sites that are relevant for receptor activation. Our data indicate that melanocortin-receptor accessory protein&#xa0;2 is an accessory protein that interacts with and influences melanocortin-4 receptor structure, biasing its signaling towards G protein-mediated effects.</p>

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MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Iqra Sohail,
  • Suli-Anne Laurin,
  • Gunnar Kleinau,
  • Vidicha Chunilal,
  • Andrew Morton,
  • Alfonso Brenlla,
  • Zeynep Cansu Uretmen Kagiali,
  • Marie-José Blouin,
  • Javier A. Tello,
  • Annette G. Beck-Sickinger,
  • Martin J. Lohse,
  • Patrick Scheerer,
  • Michel Bouvier,
  • Peter McCormick,
  • Paolo Annibale,
  • Heike Biebermann

摘要

The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor – melanocortin-receptor accessory protein 2 – Gαs complex suggests interaction sites that are relevant for receptor activation. Our data indicate that melanocortin-receptor accessory protein 2 is an accessory protein that interacts with and influences melanocortin-4 receptor structure, biasing its signaling towards G protein-mediated effects.