Search results for "RECEPTORS"
showing 10 items of 3254 documents
Apoptosis in liver disease
2001
A variety of biological functions are regulated through extracellular signals. Amongst the best studied examples is growth control, which is achieved by the regulatory function of growth factors. In recent years it has become apparent that cell death (apoptosis) is controlled in a similar fashion. Apoptosis, firstly a morphologically defined process, is a highly controlled type of cell death that plays a critical role in embryonic development, deletion of autoreactive T-cells and adult tissue homoeostasis. There is increasing evidence that derangement of the apoptotic program is the underlying cause of a series of diseases including liver diseases. The deadly program can be initiated by lig…
Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation
2001
Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evalu…
Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses
2006
Differences in the cleavage specificities of constitutive proteasomes and immunoproteasomes significantly affect the generation of MHC class I ligands and therefore the activation of CD8-positive T cells. Based on these findings, we investigated whether proteasomal specificity also influences CD8-positive T cells during thymic selection by peptides derived from self proteins. We find that one of the self peptides responsible for positive selection of ovalbumin-specific OT-1 T cells, which is derived from the f-actin capping protein (Cpalpha1), is efficiently generated only by immunoproteasomes. Furthermore, OT-1 mice backcrossed onto low molecular mass protein 7 (LMP7)-deficient mice show a…
Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition
2021
International audience; G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in non-olfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and the volume of the odorant-binding pocket, m…
High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3.
2003
We created a molecular model of the human melanocortin 4 receptor (MC4R) and introduced a series of His residues into the receptor protein to form metal ion binding sites. We were able to insert micromolar affinity binding sites for zinc between transmembrane region (TM) 2 and TM3 where the metal ion alone was able to activate this peptide binding G-protein-coupled receptor. The exact conformation of the metal ion interactions allowed us to predict the orientation of the helices, and remodeling of the receptor protein indicated that Glu100 and Ile104 in TM2 and Asp122 and Ile125 in TM3 are directed toward a putative area of activation of the receptor. The molecular model suggests that a rot…
Yeast expression of the cytokine receptor domain of the soluble interleukin-6 receptor
1996
Abstract The complex of the soluble interleukin-6 receptor (sIL-6R) and IL-6 (IL-6) is a potent agonist on cells expressing the signal transducing protein gp130. In contrast, IL-6 alone only stimulates cells which express a membrane bound form of the IL-6R and gp130. The natural occurring sIL-6R is generated by shedding of the membrane receptor and to a lesser extend by alternative splicing. We have inserted the coding sequence of the 323 amino acid residues of the human sIL-6R into an expression/secretion vector suitable for the methylotrophic yeast Pichia pastoris . We obtained, however, no detectable expression and secretion of the recombinant protein. When we used only the coding sequen…
Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.
2009
Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Recent structural studies have shown that neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the actual mechanism of receptor activation has remained elusive. Here we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p7…
Combining two mutations of human interleukin-6 that affect gp130 activation results in a potent interleukin-6 receptor antagonist on human myeloma ce…
1995
The pleiotropic cytokine interleukin-6 (IL-6) interacts with the specific ligand binding subunit (IL-6R alpha) of the IL-6 receptor, and this complex associates with the signal-transducing subunit gp130 (IL-6R beta). Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of a set of chimeric human/murine IL-6 proteins has recently allowed us to define a region (residues 43-55) within the human IL-6 protein, which is important for the interaction with gp130. Subdividing this region shows that mainly residues 50-55 of the human IL-6 are necessary for this interaction. Recently, another human IL-6 double mutant (Q159E and T162P) showed r…
Co-regulator recruitment and the mechanism of retinoic acid receptor synergy.
2002
Crystal structure and co-regulator interaction studies have led to a general mechanistic view of the initial steps of nuclear receptor (NR) action. Agonist-induced transconformation of the ligand-binding domain (holo-LBD) leads to the formation of co-activator complexes, and destabilizes the co-repressor complexes bound to the ligand-free (apo) LBD. However, the molecular basis of retinoid-X receptor (RXR) 'subordination' in heterodimers, an essential mechanism to avoid signalling pathway promiscuity, has remained elusive. RXR, in contrast to its heterodimer partner, cannot autonomously induce transcription on binding of cognate agonists. Here we show that RXR can bind ligand and recruit co…
Identification of Single Amino Acid Residues of Human IL-6 Involved in Receptor Binding and Signal Initiation
1996
The pleiotropic cytokine interleukin-6 (IL-6) has been predicted to be a protein with four antiparallel alpha-helices. On target cells, IL-6 interacts with a specific ligand binding receptor subunit (IL-6R), and this complex associates with the signal-transducing subunit gp130. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of chimeric human/murine IL-6 proteins has allowed us to define a region (residues 77-95, region 2c) within the human IL-6 protein that is important for IL-6R binding and a region (residues 50-55, region 2a2) that is important for IL-6R dependent gp130 interaction. Guided by sequence alignment and molecular…