scholarly journals Attractin' more attention – new pieces in the obesity puzzle?

2003 ◽  
Vol 376 (1) ◽  
pp. e7-e8 ◽  
Author(s):  
Giles S. H. YEO ◽  
Kenneth SIDDLE
Keyword(s):  
Transmembrane Protein ◽  
Critical Role ◽  
Family Influence ◽  
Melanocortin Receptor ◽  
Receptor Function ◽  
Melanocortin 4 Receptor ◽  
Biochemical Journal ◽  
Pharmacological Studies ◽  
G Protein Coupled

Genetic, biochemical and pharmacological studies in humans and rodents have established that signalling through the G-protein-coupled melanocortin-4 receptor (MC4R) by pro-opiomelanocortin (POMC)-derived ligands plays a critical role in the central suppression of appetite. As a consequence, malfunction of this signalling system leads to the development of obesity. It has been shown previously that melanocortin signalling can be modulated by the type 1 transmembrane protein attractin, apparently acting as a co-receptor for the inhibitory ligand agouti. Work reported in this issue of Biochemical Journal (Haqq et al.) demonstrates that the cytosolic tail of an attractin-like protein (ALP) binds directly and specifically to the C-terminal region of MC4R, raising the possibility that proteins of the attractin family influence melanocortin receptor function through multiple mechanisms.

Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Obesity ◽  
2016 ◽  
Vol 24 (9) ◽  
pp. 1976-1982 ◽  
Author(s):  
Laura Schonnop ◽  
Gunnar Kleinau ◽  
Nikolas Herrfurth ◽  
Anna-Lena Volckmar ◽  
Cigdem Cetindag ◽  
...  
Keyword(s):  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Receptor Function ◽  
Melanocortin 4 Receptor ◽  
Receptor Accessory Protein

scholarly journals The single pass membrane protein MRAP2 regulates energy homeostasis by promoting primary cilia localization of the G protein-coupled receptor MC4R

2020 ◽  
Author(s):  
Adélaïde Bernard ◽  
Irene Ojeda Naharros ◽  
Florence Bourgain-Guglielmetti ◽  
Jordi Ciprin ◽  
Xinyu Yue ◽  
...  
Keyword(s):  
G Protein ◽  
Energy Homeostasis ◽  
Primary Cilia ◽  
Melanocortin Receptor ◽  
G Protein Coupled Receptor ◽  
Promoting Effect ◽  
Receptor Associated Protein ◽  
Extracellular Signals ◽  
Melanocortin 4 Receptor ◽  
G Protein Coupled

ABSTRACTThe G protein-coupled receptor MC4R (Melanocortin-4 Receptor) and its associated protein MRAP2 (Melanocortin Receptor-Associated Protein 2) are both essential for the regulation of food intake and body weight in humans and mice. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the ciliary localization and weight-regulating function of MC4R. Our data reveal that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell systems. Our findings also demonstrate the essential role of neuronal primary cilia localization of MC4R for adequate control of energy homeostasis and the obesity-promoting effect of genetic disruption of this pathway.

scholarly journals Computational-Driven Epitope Verification and Affinity Maturation of TLR4-Targeting Antibodies

2021 ◽  
Vol 22 (11) ◽  
pp. 5989
Author(s):  
Bilal Ahmad ◽  
Maria Batool ◽  
Moon Suk Kim ◽  
Sangdun Choi
Keyword(s):  
Rational Design ◽  
Structural Integrity ◽  
Critical Role ◽  
Autoimmune Encephalitis ◽  
Affinity Maturation ◽  
Antibody Binding ◽  
Computational Techniques ◽  
Multiple Strategies ◽  
Binding Epitope

Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody–antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.

scholarly journals Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury

Cell Research ◽  
2021 ◽  
Author(s):  
Yi Fu ◽  
Yaqian Huang ◽  
Zhao Yang ◽  
Yufei Chen ◽  
Jingang Zheng ◽  
...  
Keyword(s):  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Therapeutic Strategies ◽  
At1 Receptor ◽  
Extracellular Matrix Protein ◽  
Binding Motif ◽  
Abdominal Aortic ◽  
Novel Therapeutic Strategies ◽  
G Protein Coupled

AbstractCompelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP–/– or ApoE–/– mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.

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