Arginine 125 Is an Essential Residue for the Function of MRAP2

Fullone, Maria Rosaria; Maftei, Daniela; Vincenzi, Martina; Lattanzi, Roberta; Miele, Rossella

doi:10.3390/ijms23179853

Cited by 11 publications

(6 citation statements)

References 23 publications

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“…Arginine, at position 125, was shown to play a critical role in protein conformation, dimer formation, PKR2 binding, and metabolic function. The fundamental role of this residue in MRAP2 function is confirmed by evidence that the substitution of the amino acid residue by histidine (R125H) or cysteine (R125C) is found in human patients with extreme obesity [50].…”

Section: Proteins That Stabilize Pkrs At the Cell Surfacementioning

confidence: 87%

Interaction of Prokineticin Receptors with Accessory Proteins

Lattanzi,

Miele

2023

Encyclopedia

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G protein-coupled receptors (GPCRs) are transmembrane proteins that mediate the intracellular pathway of signals not only through heterotrimeric GTP-binding proteins (G proteins) but also through their associations with a variety of additional partner proteins. Prokineticin receptors 1 (PKR1) and 2 (PKR2) are new members of the GPCRs whose ligands are the novel chemokines prokineticin 1 (PK1) and prokineticin 2 (PK2). The multiplicity of G proteins coupled to PKRs, the ability of PKR2 to heterodimerize, the interaction of PKR2 with accessory proteins, and the existence of alternative splice isoforms of PKR2/PK2 explain the complexity of the system in the signal transduction pathway and, consequently, in the modulation of various physiological and pathological functions. Knowledge of these mechanisms provides the basis for the development of targeted drugs with therapeutic efficacy in PK-dependent diseases.

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Section: Proteins That Stabilize Pkrs At the Cell Surfacementioning

confidence: 87%

Interaction of Prokineticin Receptors with Accessory Proteins

Lattanzi,

Miele

2023

Encyclopedia

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“…MRAP2 modulates various GPCRs that are important for energy homeostasis, such as the melanocortin-4 receptor, orexin, and ghrelin. MRAP2 also binds and regulates prokineticin receptors (PKRs) by reducing their signalling pathway and plasmatic membrane localisation [29,39,42,47].…”

Section: Discussionmentioning

confidence: 99%

“…We then repeated the BRET assay with PKR1 in the presence of the MRAP2 mutant obtained by deletion of the C-terminal region, termed 131CT-MRAP2. The 131CT-MRAP2 mutant is unable to affect the recruitment of β-arrestin-2 to PKR1, but inhibits receptor trafficking [38,41] without altering the activity of PKR1 [39,42,47].…”

Section: Discussionmentioning

confidence: 99%

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

Lattanzi,

Casella,

Fullone

et al. 2024

CIMB

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Melanocortin receptor accessory protein 2 (MRAP2) is a membrane protein that binds multiple G protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, including prokineticin receptors. These GPCRs are expressed both centrally and peripherally, and their endogenous ligands are prokineticin 1 (PK1) and prokineticin 2 (PK2). PKRs couple all G-protein subtypes, such as Gαq/11, Gαs, and Gαi, and recruit β-arrestins upon PK2 stimulation, although the interaction between PKR2 and β-arrestins does not trigger receptor internalisation. MRAP2 inhibits the anorexigenic effect of PK2 by binding PKR1 and PKR2. The aim of this work was to elucidate the role of MRAP2 in modulating PKR2-induced β-arrestin-2 recruitment and β-arrestin-mediated signalling. This study could allow the identification of new specific targets for potential new drugs useful for the treatment of the various pathologies correlated with prokineticin, in particular, obesity.

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“…Moreover, MRAP2 inhibits the PKR1 cell surface trafficking via its C-terminal region ( Rouault et al, 2017 ), acts as a suppressor of PKR1 signaling, and promotes food intake and weight gain, which can be reduced by activation of PKR1 ( Chaly et al, 2016 ). MRAP2 C-terminal region also binds to the N-terminal region of PKR2, preventing glycosilation and transport on the cell surface ( Verdinez and Sebag, 2021 ; Fullone et al, 2022a , b ). In ex vivo hypothalamic explants, PK2 reduces MRAP2 expression.…”

Section: Prokineticins In Obesity and Visceral Adipose Tissue Growthmentioning

confidence: 99%

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

Vincenzi,

Kremić,

Jouve

et al. 2023

Pharmacological Reviews

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The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. Significance Statement This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits “constitutive” activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.

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Arginine 125 Is an Essential Residue for the Function of MRAP2

Cited by 11 publications

References 23 publications

Interaction of Prokineticin Receptors with Accessory Proteins

Interaction of Prokineticin Receptors with Accessory Proteins

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

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