Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Teneurin Structure: Splice Variants of a Bacterial Toxin Homolog Specifies Synaptic Connections.

ABSTRACT: Teneurins are a conserved family of cell-surface adhesion molecules that mediate cellular communication, and play key roles in embryonic and neural development. Their mechanisms of action remained unclear due in part to their unknown structures. In recent years, the structures of teneurins have been reported at atomic resolutions and revealed a clear homology to bacterial Tc toxins with no similarity to other eukaryotic proteins. Another surprising observation was that alternatively spliced variants of teneurins interact with distinct ligands, and thus specify excitatory vs. inhibitory synapses. In this review, we discuss teneurin structures that together with structure-guided biochemical and functional analyses, provide insights for the mechanisms of trans-cellular communication at the synapse and other cell-cell contact sites.

SUBMITTER: Arac D

PROVIDER: S-EPMC6693077 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Teneurin Structure: Splice Variants of a Bacterial Toxin Homolog Specifies Synaptic Connections.

Araç Demet D Li Jingxian J

Frontiers in neuroscience 20190807

Teneurins are a conserved family of cell-surface adhesion molecules that mediate cellular communication, and play key roles in embryonic and neural development. Their mechanisms of action remained unclear due in part to their unknown structures. In recent years, the structures of teneurins have been reported at atomic resolutions and revealed a clear homology to bacterial Tc toxins with no similarity to other eukaryotic proteins. Another surprising observation was that alternatively spliced vari ...[more]

PMID: 31440135

Similar Datasets

TRPV1 splice variants: structure and function.

Project description:The capsaicin receptor (TRPV1) is a non-selective cation channel predominantly expressed in specialized sensory neurons that detect painful stimuli. Although its many functional roles continue to be revealed, it has been confirmed to play a critical role in the perception of peripheral inflammatory hyperalgesia and pain. TRPV1 not only is sensitized and/or activated under a wide range of conditions including inflammation and nerve injury but also undergoes changes in expressed levels in response to these same pathologic conditions. Just as our understanding of the structural requirements of TRPV1 activation has grown, there is evidence that TRPV1 forms heteromeric channel complexes. This review is focused on the structural and functional consequence of TRPV1 splice variants: VR.5'sv, TRPV1b/beta and TRPV1var. Through their co-expression and formation of heteromeric complexes with TRPV1, they have been shown to modulate TRPV1 activation. Moreover, TRPV1 splice variant subunits may also contribute unique properties of activation such as the detection of hypertonic conditions.

| S-EPMC3888216 | biostudies-literature

Teneurin-3 specifies morphological and functional connectivity of retinal ganglion cells in the vertebrate visual system.

Project description:A striking feature of the CNS is the precise wiring of its neuronal connections. During vertebrate visual system development, different subtypes of retinal ganglion cells (RGCs) form specific connections with their corresponding synaptic partners. However, the underlying molecular mechanisms remain to be fully elucidated. Here, we report that the cell-adhesive transmembrane protein Teneurin-3 (Tenm3) is required by zebrafish RGCs for acquisition of their correct morphological and functional connectivity in vivo. Teneurin-3 is expressed by RGCs and their presynaptic amacrine and postsynaptic tectal cell targets. Knockdown of Teneurin-3 leads to RGC dendrite stratification defects within the inner plexiform layer, as well as mistargeting of dendritic processes into outer portions of the retina. Moreover, a subset of RGC axons exhibits tectal laminar arborization errors. Finally, functional analysis of RGCs targeting the tectum reveals a selective deficit in the development of orientation selectivity after Teneurin-3 knockdown. These results suggest that Teneurin-3 plays an instructive role in the functional wiring of the vertebrate visual system.

| S-EPMC3898612 | biostudies-literature

Splice variants of enigma homolog, differentially expressed during heart development, promote or prevent hypertrophy.

Project description:Proteins with a PDZ (for PSD-95, DLG, ZO-1) and one to three LIM (for Lin11, Isl-1, Mec-3) domains are scaffolding sarcomeric and cytoskeletal elements that form structured muscle fibres and provide for the link to intracellular signalling by selectively associating protein kinases, ion channels, and transcription factors with the mechanical stress-strain sensors. Enigma homolog (ENH) is a PDZ-LIM protein with four splice variants: ENH1 with an N-terminal PDZ domain and three C-terminal LIM domains and ENH2, ENH3, and ENH4 without LIM domains. We addressed the functional role of ENH alternative splicing.We studied the expression of the four ENH isoforms in the heart during development and in a mouse model of heart hypertrophy. All four isoforms are expressed in the heart but the pattern of expression is clearly different between embryonic, neonatal, and adult stages. ENH1 appears as the embryonic isoform, whereas ENH2, ENH3, and ENH4 are predominant in adult heart. Moreover, alternative splicing of ENH was changed following induction of heart hypertrophy, producing an ENH isoform pattern similar to that of neonatal heart. Next, we tested a possible causal role of ENH1 and ENH4 in the development of cardiac hypertrophy. When overexpressed in rat neonatal cardiomyocytes, ENH1 promoted the expression of hypertrophy markers and increased cell volume, whereas, on the contrary, ENH4 overexpression prevented these changes.Antagonistic splice variants of ENH may play a central role in the adaptive changes of the link between mechanical stress-sensing and signalling occurring during embryonic development and/or heart hypertrophy.

| S-EPMC2868178 | biostudies-other

Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice.

Project description:Synapse assembly requires trans-synaptic signals between the pre- and postsynapse, but our understanding of the essential organizational molecules involved in this process remains incomplete. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with ?-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection.

| S-EPMC3326183 | biostudies-literature

Structure of a bacterial toxin-activating acyltransferase.

Project description:Secreted pore-forming toxins of pathogenic Gram-negative bacteria such as Escherichia coli hemolysin (HlyA) insert into host-cell membranes to subvert signal transduction and induce apoptosis and cell lysis. Unusually, these toxins are synthesized in an inactive form that requires posttranslational activation in the bacterial cytosol. We have previously shown that the activation mechanism is an acylation event directed by a specialized acyl-transferase that uses acyl carrier protein (ACP) to covalently link fatty acids, via an amide bond, to specific internal lysine residues of the protoxin. We now reveal the 2.15-Å resolution X-ray structure of the 172-aa ApxC, a toxin-activating acyl-transferase (TAAT) from pathogenic Actinobacillus pleuropneumoniae. This determination shows that bacterial TAATs are a structurally homologous family that, despite indiscernible sequence similarity, form a distinct branch of the Gcn5-like N-acetyl transferase (GNAT) superfamily of enzymes that typically use acyl-CoA to modify diverse bacterial, archaeal, and eukaryotic substrates. A combination of structural analysis, small angle X-ray scattering, mutagenesis, and cross-linking defined the solution state of TAATs, with intermonomer interactions mediated by an N-terminal ?-helix. Superposition of ApxC with substrate-bound GNATs, and assay of toxin activation and binding of acyl-ACP and protoxin peptide substrates by mutated ApxC variants, indicates the enzyme active site to be a deep surface groove.

| S-EPMC4466738 | biostudies-literature

Teneurin Structures Are Composed of Ancient Bacterial Protein Domains.

Project description:Pioneering bioinformatic analysis using sequence data revealed that teneurins evolved from bacterial tyrosine-aspartate (YD)-repeat protein precursors. Here, we discuss how structures of the C-terminal domain of teneurins, determined using X-ray crystallography and electron microscopy, support the earlier findings on the proteins' ancestry. This chapter describes the structure of the teneurin scaffold with reference to a large family of teneurin-like proteins that are widespread in modern prokaryotes. The central scaffold of modern eukaryotic teneurins is decorated by additional domains typically found in bacteria, which are re-purposed in eukaryotes to generate highly multifunctional receptors. We discuss how alternative splicing contributed to further diversifying teneurin structure and thereby function. This chapter traces the evolution of teneurins from a structural point of view and presents the state-of-the-art of how teneurin function is encoded by its specific structural features.

| S-EPMC6425310 | biostudies-literature

Discs Large Homolog 1 Splice Variants Regulate p38-Dependent and -Independent Effector Functions in CD8+ T Cells.

Project description:Functionally diverse CD8+ T cells develop in response to antigenic stimulation with differing capacities to couple TCR engagement to downstream signals and functions. However, mechanisms of diversifying TCR signaling are largely uncharacterized. Here we identified two alternative splice variants of scaffold protein Dlg1, Dlg1AB and Dlg1B, that diversify signaling to regulate p38-dependent and -independent effector functions in CD8+ T cells. Dlg1AB, but not Dlg1B associated with Lck, coupling TCR stimulation to p38 activation and proinflammatory cytokine production. Conversely, both Dlg1AB and Dlg1B mediated p38-independent degranulation. Degranulation depended on a Dlg1 fragment containing an intact Dlg1SH3-domain and required the SH3-ligand WASp. Further, Dlg1 controlled WASp activation by promoting TCR-triggered conformational opening of WASp. Collectively, our data support a model where Dlg1 regulates p38-dependent proinflammatory cytokine production and p38-independent cytotoxic granule release through the utilization of alternative splice variants, providing a mechanism whereby TCR engagement couples downstream signals to unique effector functions in CD8+ T cells.

| S-EPMC4505885 | biostudies-literature

Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse.

Project description:Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large ? barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a ? propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the ? propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.

| S-EPMC5912346 | biostudies-literature

Crystal structure of an asymmetric trimer of a bacterial glutamate transporter homolog.

Project description:We report a structure of a trimeric glutamate transporter homolog from Pyrococcus horikoshii with two protomers in an inward facing state and the third in an intermediate conformation between the outward and inward facing states. The intermediate shows a cavity in the thinnest region of the transporter, which is potentially accessible to extracellular and cytoplasmic solutions. Our findings suggest a structural principle by which transport intermediates may mediate uncoupled permeation of polar solutes.

| S-EPMC3633560 | biostudies-literature

Redundancy in synaptic connections enables neurons to learn optimally.

Project description:Recent experimental studies suggest that, in cortical microcircuits of the mammalian brain, the majority of neuron-to-neuron connections are realized by multiple synapses. However, it is not known whether such redundant synaptic connections provide any functional benefit. Here, we show that redundant synaptic connections enable near-optimal learning in cooperation with synaptic rewiring. By constructing a simple dendritic neuron model, we demonstrate that with multisynaptic connections synaptic plasticity approximates a sample-based Bayesian filtering algorithm known as particle filtering, and wiring plasticity implements its resampling process. Extending the proposed framework to a detailed single-neuron model of perceptual learning in the primary visual cortex, we show that the model accounts for many experimental observations. In particular, the proposed model reproduces the dendritic position dependence of spike-timing-dependent plasticity and the functional synaptic organization on the dendritic tree based on the stimulus selectivity of presynaptic neurons. Our study provides a conceptual framework for synaptic plasticity and rewiring.

| S-EPMC6055135 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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