Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structural basis for CD97 recognition of the decay-accelerating factor CD55 suggests mechanosensitive activation of adhesion GPCRs.

ABSTRACT: The adhesion G protein-coupled receptor CD97 and its ligand complement decay-accelerating factor CD55 are important binding partners in the human immune system. Dysfunction in this binding has been linked to immune disorders such as multiple sclerosis and rheumatoid arthritis, as well as various cancers. Previous literatures have indicated that the CD97 includes 3 to 5 epidermal growth factor (EGF) domains at its N terminus and these EGF domains can bind to the N-terminal short consensus repeat (SCR) domains of CD55. However, the details of this interaction remain elusive, especially why the CD55 binds with the highest affinity to the shortest isoform of CD97 (EGF_1,2,5). Herein, we designed a chimeric expression construct with the EGF_1,2,5 domains of CD97 and the SCR_1-4 domains of CD55 connected by a flexible linker and determined the complex structure by crystallography. Our data reveal that the two proteins adopt an overall antiparallel binding mode involving the SCR_1-3 domains of CD55 and all three EGF domains of CD97. Mutagenesis data confirmed the importance of EGF₅ in the interaction and explained the binding specificity between CD55 and CD97. The architecture of CD55-CD97 binding mode together with kinetics suggests a force-resisting shearing stretch geometry when forces applied to the C termini of both proteins in the circulating environment. The potential of the CD55-CD97 complex to withstand tensile force may provide a basis for the mechanosensing mechanism for activation of adhesion G protein-coupled receptors.

SUBMITTER: Niu M

PROVIDER: S-EPMC8191316 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Molecular and functional analysis of mouse decay accelerating factor (CD55).

Project description:Molecular cloning of mouse decay accelerating factor (DAF; CD55) predicted two forms of the molecule, one transmembrane (TM) and the other glycosylphosphatidylinositol (GPI)-anchored; these are encoded by separate genes termed Daf-GPI and Daf-TM. In the present study several additional isoforms of mouse DAF, generated by alternative splicing from these genes, are described. Northern-blot analysis of RNA and reverse transcriptase-PCR from various tissues indicated that spleen and testis expressed high levels of DAF, which comprised several species. These species were cloned and sequence analysis revealed various novel forms in addition to those previously reported. Two novel forms were derived from the Daf-TM gene but the transmembrane sequence defined previously was replaced by a unique GPI-anchor addition sequence; one clone also had part of the serine/threonine/proline (STP) region deleted. A third clone, encoding a transmembrane protein, was also derived from this gene but the entire STP region was deleted. A fourth clone, derived from the Daf-GPI gene, contained a novel C-terminal sequence, suggestive of a secreted form of the protein. Two DAF cDNAs (TM and GPI-anchored) were stably expressed in Chinese hamster ovary cells. When these cells were attacked with mouse or rat complement and analysed for C3b deposition, DAF-transfected cells had greatly reduced C3b deposition compared with controls. Transfection with DAF also conferred protection from complement in a cell-lysis assay, and a soluble, recombinant form of mouse DAF inhibited complement in a haemolytic assay.

| S-EPMC1220423 | biostudies-other

Agents which upregulate CD55 [decay accelerating factor (DAF)] expression [Array]

Project description:(Submitter supplied) Identification of transcription factors (TFs) which upregulate human CD55 expression. CD55 was originally described as a cellular complement regulator that protects self-cells from autologous complement attack. It is now known as cellular regulator which controls many functions of cells, as examples T cell commitment to T effector cells vs Foxp3+ T regulatory cells, B2 cell Ab production, and receptor tyrosine kinase (RTK) growth factor receptor function. Overlap of the arrays identified the immunosuppressive TF Kruppel Like Factor 4 (KLF4). The current study shows that CD55 functions jointly with KLF4.

2024-02-12 | GSE255080 | GEO

Adhesion GPCR CD97 promotes spleen dendritic cell retention and function through sensing of CD55-expressing red blood cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-23 | GSE188835 | GEO

G Protein-Coupling of Adhesion GPCRs ADGRE2/EMR2 and ADGRE5/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody.

Project description:The experimental evidence that Adhesion G Protein-Coupled Receptors (aGPCRs) functionally couple to heterotrimeric G proteins has been emerging in incremental steps, but attributing biological significance to their G protein signalling function still presents a major challenge. Here, utilising activated truncated forms of the receptors, we show that ADGRE2/EMR2 and ADGRE5/CD97 are G protein-coupled in a variety of recombinant systems. In a yeast-based assay, where heterologous GPCRs are coupled to chimeric G proteins, EMR2 showed broad G protein-coupling, whereas CD97 coupled more specifically to G?12, G?13, G?14 and G?z chimeras. Both receptors induced pertussis-toxin (PTX) insensitive inhibition of cyclic AMP (cAMP) levels in mammalian cells, suggesting coupling to G?z. EMR2 was shown to signal via G?16, and via a G?16/G?z chimera, to stimulate IP1 accumulation. Finally, using an NFAT reporter assay, we identified a polyclonal antibody that activates EMR2 G protein signalling in vitro. Our results highlight the potential for the development of soluble agonists to understand further the biological effects and therapeutic opportunities for ADGRE receptor-mediated G protein signalling.

| S-EPMC6976652 | biostudies-literature

Agents which upregulate CD55 [decay accelerating factor (DAF)] expression [Array]

Project description:Agents which upregulate CD55 [decay accelerating factor (DAF)] expression [Array]

| PRJNA1073479 | ENA

Discovery, linkage disequilibrium and association analyses of polymorphisms of the immune complement inhibitor, decay-accelerating factor gene (DAF/CD55) in type 1 diabetes.

Project description:BackgroundType 1 diabetes (T1D) is a common autoimmune disease resulting from T-cell mediated destruction of pancreatic beta cells. Decay accelerating factor (DAF, CD55), a glycosylphosphatidylinositol-anchored membrane protein, is a candidate for autoimmune disease susceptibility based on its role in restricting complement activation and evidence that DAF expression modulates the phenotype of mice models for autoimmune disease. In this study, we adopt a linkage disequilibrium (LD) mapping approach to test for an association between the DAF gene and T1D.ResultsInitially, we used HapMap II genotype data to examine LD across the DAF region. Additional resequencing was required, identifying 16 novel polymorphisms. Combining both datasets, a LD mapping approach was adopted to test for association with T1D. Seven tag SNPs were selected and genotyped in case-control (3,523 cases and 3,817 controls) and family (725 families) collections.ConclusionWe obtained no evidence of association between T1D and the DAF region in two independent collections. In addition, we assessed the impact of using only HapMap II genotypes for the selection of tag SNPs and, based on this study, found that HapMap II genotypes may require additional SNP discovery for comprehensive LD mapping of some genes in common disease.

| S-EPMC1479364 | biostudies-literature

Helix 8 is the essential structural motif of mechanosensitive GPCRs.

Project description:G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.

| S-EPMC6923424 | biostudies-literature

Revisiting the classification of adhesion GPCRs.

Project description:G protein-coupled receptors (GPCRs) are encoded by over 800 genes in the human genome. Motivated by different scientific rationales, the two classification systems that are mainly in use, the ABC and GRAFS systems, organize GPCRs according to their pharmacological features and phylogenetic relations, respectively. Within those systems, adhesion GPCRs (aGPCRs) constitute a group of over 30 mammalian homologs, most of which are still orphans with undefined activating signals and signal transduction properties. Previous efforts have further subdivided mammalian aGPCRs into nine subfamilies to indicate phylogenetic relationships. However, this subclassification scheme has shortcomings and inconsistencies that require attention. Here, we have reassessed the phylogenetic relationships of aGPCRs from vertebrate and invertebrate species. Our findings confirm that secretin receptor-like GPCRs most probably emerged from ancestral aGPCRs. We show that reassignment of several aGPCRs to families essentially requires input from functional data. Our analyses establish the need for introducing novel aGPCR subfamilies due to aGPCR sequences from invertebrate species that are not readily assignable to any existing subfamily. We conclude that the current classification systems ought to be updated to consider an unambiguous taxonomy of a hierarchically organized classification and pharmacological properties, and to accommodate phylogenetic affiliations between aGPCR genes within mammals and across the animal kingdom.

| S-EPMC6900090 | biostudies-literature

Role of transcription factor Sp1 and RNA binding protein HuR in the downregulation of Dr+ Escherichia coli receptor protein decay accelerating factor (DAF or CD55) by nitric oxide.

Project description:We previously reported that nitric oxide (NO) reduces the rate of bacteremia and maternal mortality in pregnant rats with uterine infection by Escherichia coli expressing the Dr Fimbria (Dr(+) ). The epithelial invasion of Dr(+) E. coli is dependent on the expression level of its cellular receptor decay accelerating factor (DAF). NO reduces the rate of bacteremia by downregulating the expression of DAF. In this study, we elucidated the role of transcription factor Sp1 and RNA binding protein HuR in the downregulation of human DAF by NO. We generated a series of deletion mutant constructs of DAF gene 5'-untranslated region and mapped the NO-response region upstream to the core promoter region of the DAF gene. One of the several Sp1 binding sites in the DAF 5'-untranslated region was located within the NO-response region. The binding of Sp1 to this site was inhibited by NO. Furthermore, NO also promoted the degradation of DAF mRNA. The 3'-untranslated region of DAF harbors an AU-rich element and this element destabilized the mRNA transcript. NO promoted the rapid degradation of DAF mRNA by inhibiting the binding of mRNA stabilizing protein HuR to this AU-rich region. The inhibition of binding of HuR to the AU-rich region was due to the S-nitrosylation of one or more cysteine residues by NO. Thus, these data reveal the molecular mediators of transcriptional and post-transcriptional regulation of DAF by NO with implications in pathophysiology related to DAF.

| S-EPMC3558599 | biostudies-literature

Dynamics of Mechanosensitive Nascent Adhesion Formation.

Project description:Cellular migration is a tightly regulated process that involves actin cytoskeleton, adaptor proteins, and integrin receptors. Forces are transmitted extracellularly through protein complexes of these molecules, called adhesions. Adhesions anchor the cell to its substrate, allowing it to migrate. In Chinese hamster ovary cells, three classes of adhesion can be identified: nascent adhesions (NAs), focal complexes, and focal adhesions, ranked here ascendingly based on size and stability. To understand the dynamics and mechanosensitive properties of NAs, a biophysical model of these NAs as colocalized clusters of integrins and adaptor proteins is developed. The model is then analyzed to characterize the dependence of NA area on biophysical parameters that regulate the number of integrins and adaptor proteins within NAs through a mechanosensitive coaggregation mechanism. Our results reveal that NA formation is triggered beyond a threshold of adaptor protein, integrin, or extracellular ligand densities, with these three factors listed in descending order of their relative influence on NA area. Further analysis of the model also reveals that an increase in coaggregation or reductions in integrin mobility inside the adhesion potentiate NA formation. By extending the model to consider the mechanosensitivity of the integrin bond, we identify mechanical stress, rather than mechanical load, as a permissive mechanical parameter that allows for noise-dependent and independent NA assembly, despite both parameters producing a bistable switch possessing a hysteresis. Stochastic simulations of the model confirm these results computationally. This study thus provides insight into the mechanical conditions defining NA dynamics.

| S-EPMC6818182 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data