Arrestin makes T cells stop and become active.
Ontology highlight
ABSTRACT:
SUBMITTER: Gurevich VV
PROVIDER: S-EPMC3989646 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
Publications
Arrestin makes T cells stop and become active.
Gurevich Vsevolod V VV Gurevich Eugenia V EV
The EMBO journal 20140206 6
T-cell activation requires signaling by T-cell receptors (TCRs) that bind antigen on the antigen-presenting cells (APCs) at the immunological synapse (IS). Sustained signaling requires continuous supply of new TCRs to the IS. In this issue of The EMBO Journal, Fernández-Arenas et al (2014) describe a novel role of β-arrestin-1 at the IS periphery: endocytosis of TCRs and chemokine CXCR4 receptors. Internalized TCRs are then delivered to the IS, where they engage antigen and support prolonged sig ...[more]
Similar Datasets
Project description:Chromatin structure and underlying DNA accessibility is modulated by the incorporation of histone variants. H2A.Z, a variant of the H2A core histone family, plays a distinct and essential role in a diverse set of biological functions including gene regulation and maintenance of heterochromatin-euchromatin boundaries. Although it is currently unclear how the replacement of H2A with H2A.Z can regulate gene expression, the variance in their amino acid sequence likely contributes to their functional differences. To tease apart regions of H2A.Z that confer its unique identity, a set of plasmids expressing H2A-H2A.Z hybrids from the native H2A.Z promoter were examined for their ability to recapitulate H2A.Z function. First, we found that the H2A.Z M6 region was necessary and sufficient for interaction with the SWR1-C chromatin remodeler. Remarkably, the combination of only 9 amino acid changes, the H2A.Z M6 region, K79 and L81 (two amino acids in the α2-helix), were sufficient to fully rescue growth phenotypes of the htz1Δ mutant. Furthermore, combining three unique H2A.Z regions (K79 and L81, M6, C-terminal tail) was sufficient for expression of H2A.Z-dependent heterochromatin-proximal genes and GAL1 derepression. Surprisingly, hybrid constructs that restored the transcription of H2A.Z-dependent genes, did not fully recapitulate patterns of H2A.Z-specific enrichment at the tested loci. This suggested that H2A.Z function in transcription regulation may be at least partially independent of its specific localization in chromatin. Together, this work has identified three regions that can confer specific H2A.Z-identity to replicative H2A, furthering our understanding of what makes a histone variant a variant.
| S-EPMC8675926 | biostudies-literature
Project description:Diseases in humans, animals and plants remain an important challenge in our society. Effective control of invasive pathogens often requires coordinated concerted action of a large group of stakeholders. Both epidemiological and human behavioural factors influence the outcome of a disease control campaign. In mathematical models that are frequently used to guide such campaigns, human behaviour is often ill-represented, if at all. Existing models of human, animal and plant disease that do incorporate participation or compliance are often driven by pay-offs or direct observations of the disease state. It is however very well known that opinion is an important driving factor of human decision making. Here we consider the case study of Citrus Huanglongbing disease (HLB), which is an acute bacterial disease that threatens the sustainability of citrus production across the world. We show how by coupling an epidemiological model of this invasive disease with an opinion dynamics model we are able to answer the question: What makes or breaks the effectiveness of a disease control campaign? Frequent contact between stakeholders and advisors is shown to increase the probability of successful control. More surprisingly, we show that informing stakeholders about the effectiveness of control methods is of much greater importance than prematurely increasing their perceptions of the risk of infection. We discuss the overarching consequences of this finding and the effect on human as well as plant disease epidemics.
| S-EPMC7004315 | biostudies-literature
Project description:Arrestins regulate signaling and trafficking of G protein-coupled receptors by virtue of their preferential binding to the phosphorylated active form of the receptor. To identify sites in arrestin involved in receptor interaction, a nitroxide-containing side chain was introduced at each of 28 different positions in visual arrestin, and the dynamics of the side chain was used to monitor arrestin interaction with phosphorylated forms of its cognate receptor, rhodopsin. At physiological concentrations, visual arrestin associates with both inactive dark phosphorylated rhodopsin (P-Rh) and light-activated phosphorylated rhodopsin (P-Rh*). Residues distributed over the concave surfaces of the two arrestin domains are involved in weak interactions with both states of phosphorhodopsin, and the flexible C-terminal sequence (C-tail) of arrestin becomes dynamically disordered in both complexes. A large-scale movement of the C-tail is demonstrated by direct distance measurements using a doubly labeled arrestin with one nitroxide in the C-tail and the other in the N-domain. Despite some overlap, the molecular "footprint" of arrestin bound to P-Rh and P-Rh* is different, showing the structure of the complexes to be unique. Strong immobilizing interactions with residues in a highly flexible loop between beta-strands V and VI are only observed in complex with the activated state. This result identifies this loop as a key recognition site in the arrestin-P-Rh* complex and supports the view that flexible sequences are key elements in protein-protein interactions.
| S-EPMC1458767 | biostudies-literature
Project description:In rod photoreceptors, deactivation of the light-activated G-protein-coupled receptor rhodopsin (R*) is initiated by phosphorylation and completed through subsequent binding of visual arrestin (Arr1). The in vivo kinetics of these individual interactions have proven difficult to determine with precision since R* lifetime is much shorter than the lifetimes of downstream G-protein and effector molecules. Here, we have used a transgenic mouse line with accelerated downstream deactivation kinetics to reveal the contribution of Arr1 binding to the overall time course of rhodopsin deactivation. Photoresponses revealed that the lifetime of R* is significantly increased in rods that express half of the normal amount of Arr1, in a manner consistent with a twofold decrease in the rate of Arr1 binding across a wide range of flash strengths. A basic model of photoresponse deactivation consistent with established photoreceptor biochemistry shows that R* phosphorylation and Arr1 binding occur with a time constant of approximately 40 ms in wild-type mouse rods, much faster than previous estimates.
| S-EPMC2841010 | biostudies-literature
Project description:G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of "zero functional G" at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of G? proteins, along with pertussis toxin-mediated inactivation of Gi/o. Together with HEK293 cells lacking ?-arrestins ("zero arrestin"), we systematically dissect G protein- from arrestin-driven signaling outcomes for a broad set of GPCRs. We use biochemical, biophysical, label-free whole-cell biosensing and ERK phosphorylation to identify four salient features for all receptors at "zero functional G": arrestin recruitment and internalization, but-unexpectedly-complete failure to activate ERK and whole-cell responses. These findings change our understanding of how GPCRs function and in particular of how they activate ERK1/2.
| S-EPMC5780443 | biostudies-literature
Project description:Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs). Arrestin binds to active phosphorylated GPCRs with higher affinity than to all other functional forms of the receptor, including inactive phosphorylated and active unphosphorylated. The selectivity of arrestins suggests that they must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently. Simultaneous engagement of both sensors enables arrestin transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that brings additional elements of the arrestin molecule, including the middle loop, in contact with a GPCR, thereby stabilizing the complex. Here, we review structural and mutagenesis data that identify these two sensors and additional receptor-binding elements within the arrestin molecule. While most data were obtained with the arrestin-1-rhodopsin pair, the evidence suggests that all arrestins use similar mechanisms to achieve preferential binding to active phosphorylated GPCRs.
| S-EPMC8621391 | biostudies-literature
Project description:Transcriptional silencing of terminal differentiation genes by the Polycomb group (PcG) machinery is emerging as a key feature of precursor cells in stem cell lineages. How, then, is this epigenetic silencing reversed for proper cellular differentiation? Here we investigate how the developmental program reverses local PcG action to allow expression of terminal differentiation genes in the Drosophila male germline stem cell lineage. We find that the silenced state, set up in precursor cells, is relieved through developmentally regulated sequential events at promoters once cells commit to spermatocyte differentiation. The programmed events include global down-regulation of PRC2, recruitment of hypophosphorylated RNA Polymerase II (Pol II) to promoters, as well as expression and action of cell-type specific homologs of subunits of TFIID (tTAFs). In addition, action of tMAC, a tissue specific version of the MIP/dREAM complex, is required both for recruitment of tTAFs to target differentiation genes and for proper cell-type specific localization of PRC1 components and tTAFs to the spermatocyte nucleolus. Together, action of the tMAC and tTAF cell-type specific chromatin and transcription machinery leads to loss of Polycomb and release of Pol II from the promoter of terminal differentiation genes to elongation, allowing robust transcription of the terminal differentiation genes. Total RNA from approximately 200 pairs of fly testes (bam1/bam-delta-86; aly2/aly5P; sa1/sa2; y,w) was extracted using TRIzol (Invitrogen, #15596-018, Carlsbad, CA, USA) following the manufacturer's instructions. The genomic DNA was degraded using 2 Units of DNase I (Fermentas, #EN0521, Glen Burnie, MD, USA) at 37 degreeC for 20 minutes. RNA integrity was checked by gel electrophoresis (1% agarose). Approximately 4 μg of total RNA from each biological replicate were used to generate labeling probes to hybridize with the Affymetix GeneChip Drosophila Genome 2.0 Array according to the Affymetrix protocol. Three biological replicates were performed for each genotype. Microarray hybridization was processed at the Core Facility at the Stanford University School of Medicine and the raw data were exported from the Affymetrix Microarray Suite (MAS). The CEL files were used for signal normalization with RMA as part of the limma package from the Bioconductor R packages (http://www.bioconductor.org).
2011-07-14 | E-GEOD-28728 | biostudies-arrayexpress
Project description:Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development. We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.
| S-EPMC3883704 | biostudies-literature
Project description:Signaling of the prototypical G protein-coupled receptor (GPCR) rhodopsin through its cognate G protein transducin (Gt) is quenched when arrestin binds to the activated receptor. Although the overall architecture of the rhodopsin/arrestin complex is known, many questions regarding its specificity remain unresolved. Here, using FTIR difference spectroscopy and a dual pH/peptide titration assay, we show that rhodopsin maintains certain flexibility upon binding the "finger loop" of visual arrestin (prepared as synthetic peptide ArrFL-1). We found that two distinct complexes can be stabilized depending on the protonation state of E3.49 in the conserved (D)ERY motif. Both complexes exhibit different interaction modes and affinities of ArrFL-1 binding. The plasticity of the receptor within the rhodopsin/ArrFL-1 complex stands in contrast to the complex with the C terminus of the Gt ?-subunit (G?CT), which stabilizes only one specific substate out of the conformational ensemble. However, Gt ?-subunit binding and both ArrFL-1-binding modes involve a direct interaction to conserved R3.50, as determined by site-directed mutagenesis. Our findings highlight the importance of receptor conformational flexibility and cytoplasmic proton uptake for modulation of rhodopsin signaling and thereby extend the picture provided by crystal structures of the rhodopsin/arrestin and rhodopsin/ArrFL-1 complexes. Furthermore, the two binding modes of ArrFL-1 identified here involve motifs of conserved amino acids, which indicates that our results may have elucidated a common modulation mechanism of class A GPCR-G protein/-arrestin signaling.
| S-EPMC5868258 | biostudies-literature
Project description:The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of ?-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of ?-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate ?-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of ?-arrestin-1. The structure of the ?-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in ?-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of ?-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on ?-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.
| S-EPMC3654799 | biostudies-literature