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14 pages, 2821 KiB

Open AccessFeature PaperArticle

Structure/Function Studies on the Activation Motif of Two Non-Mammalian Mrap1 Orthologs, and Observations on the Phylogeny of Mrap1, Including a Novel Characterization of an Mrap1 from the Chondrostean Fish, Polyodon spathula

by Robert M. Dores, Greer McKinley, Audrey Meyers, Morgan Martin and Ciaran A. Shaughnessy

Biomolecules 2022, 12(11), 1681; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12111681 - 12 Nov 2022

Cited by 4 | Viewed by 1247

Abstract

In derived bony vertebrates, activation of the melanocortin-2 receptor (Mc2r) by its ACTH ligand requires chaperoning by the Mc2r accessory protein (Mrap1). The N-terminal domain of the non-mammalian tetrapod MRAP1 from chicken (c; Gallus gallus) has the putative activation motif, W¹⁸ [...] Read more.

In derived bony vertebrates, activation of the melanocortin-2 receptor (Mc2r) by its ACTH ligand requires chaperoning by the Mc2r accessory protein (Mrap1). The N-terminal domain of the non-mammalian tetrapod MRAP1 from chicken (c; Gallus gallus) has the putative activation motif, W¹⁸D¹⁹Y²⁰I²¹, and the N-terminal domain in the neopterygian ray-finned fish Mrap1 from bowfin (bf; Amia calva) has the putative activation motif, Y¹⁸D¹⁹Y²⁰I²¹. The current study used an alanine-substitution paradigm to test the hypothesis that only the Y²⁰ position in the Mrap1 ortholog of these non-mammalian vertebrates is required for activation of the respective Mc2r ortholog. Instead, we found that for cMRAP1, single alanine-substitution resulted in a gradient of inhibition of activation (Y²⁰ >> D¹⁹ = W¹⁸ > I²¹). For bfMrap1, single alanine-substitution also resulted in a gradient of inhibition of activation (Y²⁰ >> D¹⁹ > I²¹ > Y¹⁸). This study also included an analysis of Mc2r activation in an older lineage of ray-finned fish, the paddlefish (p), Polyodon spathula (subclass Chondronstei). Currently no mrap1 gene has been found in the paddlefish genome. When pmc2r was expressed alone in our CHO cell/cAMP reporter gene assay, no activation was observed following stimulation with ACTH. However, when pmc2r was co-expressed with either cmrap1 or bfmrap1 robust dose response curves were generated. These results indicate that the formation of an Mc2r/Mrap1 heterodimer emerged early in the radiation of the bony vertebrates. Full article

(This article belongs to the Special Issue The Melanocortin System: From Ligands to Receptors and Accessory Systems)

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Review

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20 pages, 2537 KiB

Open AccessReview

Melanogenesis and the Targeted Therapy of Melanoma

by Cang Li, Le Kuai, Rutao Cui and Xiao Miao

Biomolecules 2022, 12(12), 1874; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12121874 - 14 Dec 2022

Cited by 11 | Viewed by 3508

Abstract

Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we [...] Read more.

Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we reviewed the current available literatures on the mechanisms of melanogenesis, including the signaling pathways of UVR-induced pigment production, MC1R’s central determinant roles and MITF as a master transcriptional regulator in melanogenesis. Moreover, we further highlighted the role of targeting BRAF, NRAS and MC1R in melanoma prevention and treatment. The combination therapeutics of immunotherapy and targeted kinase inhibitors are becoming the newest therapeutic option in advanced melanoma. Full article

(This article belongs to the Special Issue The Melanocortin System: From Ligands to Receptors and Accessory Systems)

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23 pages, 1456 KiB

Open AccessFeature PaperReview

Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin

by Xiao-Chen Yuan and Ya-Xiong Tao

Biomolecules 2022, 12(10), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101407 - 01 Oct 2022

Cited by 3 | Viewed by 3052

Abstract

The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three [...] Read more.

The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs). Full article

(This article belongs to the Special Issue The Melanocortin System: From Ligands to Receptors and Accessory Systems)

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