The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ ADGRG6 as Allosteric Force Integrator

The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner

Signal integration by lipid-mediated spatial cross talk between Ras nanoclusters

Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters however has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions indicating that Ras proteins engage in isoform-selective lipid sorting, and accounting for different signal outputs from each Ras isoform. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experiment reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important, previously unexplored opportunities for signal integration and signal processing

A Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Route to the Carbazole Natural Products 3‑Methyl‑9<i>H</i>‑carbazole, Glycoborine, Glycozoline, Clauszoline K, Mukonine, and Karapinchamine A

The title natural products <b>2</b>–<b>7</b> have been prepared by reductive cyclization of the relevant 2-arylcyclohex-2-en-1-one (e.g. <b>20</b>) to the corresponding tetrahydrocarbazole and dehydrogenation (aromatization) of this to give the target carbazole (e.g. <b>4</b>). Compounds such as <b>20</b> were prepared using a palladium-catalyzed Ullmann cross-coupling reaction between the appropriate 2-iodocyclohex-2-en-1-one and <i>o</i>-halonitrobenzene

Osteuropäische 24-Stunden-Betreuerinnen - Gestalterinnen ihrer eigenen Lebenslage

Pflegearrangements wie die 24-Stunden-Betreuung in der Häuslichkeit einer pflegebedürftigen Person im Ausland verändern maßgeblich die Lebenssituation derjenigen, die diese Leistung anbieten, da sie in der Regel weite geografische Entfernung zwischen dem Wohnort im Heimatland und Einsatzort bewältigen müssen. Die Abwesenheit von zu Hause verlangt von ihnen besondere Kompetenzen sowie Handlungsfähigkeit für die Gestaltung der ihnen zur Verfügung stehenden Handlungsspielräume, vor allem auf der Beziehungsebene, aber auch in den anderen Lebensbereichen wie z. B. Freizeit, Bildung, Wohnen, Beschäftigung etc. Wie groß oder begrenzt die Handlungsspielräume der Pendlerinnen sind, wie sich das Pendeln und der Beschäftigungsstatus »irregulär«/»regulär« auf deren Handlungsmöglichkeiten auswirken und wie die Pendlerinnen ihre Handlungsspielräume nutzen sind Inhalte des folgenden Beitrags