RESUMO
Key cellular functions depend on the transduction of extracellular mechanical signals by specialized membrane receptors including adhesion G-protein coupled receptors (aGPCRs). While recently solved structures support aGPCR activation through shedding of the extracellular GAIN domain, the molecular mechanisms underpinning receptor mechanosensing remain poorly understood. When probed using single-molecule atomic force spectroscopy and molecular simulations, ADGRG1 GAIN dissociated from its tethered agonist at forces significantly higher than other reported signaling mechanoreceptors. Strong mechanical resistance was achieved through specific structural deformations and force propagation pathways under mechanical load. ADGRG1 GAIN variants computationally designed to lock the alpha and beta subdomains and rewire mechanically-induced structural deformations were found to modulate the GPS-Stachel rupture forces. Our study provides unprecedented insights into the molecular underpinnings of GAIN mechanical stability and paves the way for engineering mechanosensors, better understanding aGPCR function, and informing drug-discovery efforts targeting this important receptor class.
RESUMO
A water-soluble fraction from the marine diatom Haslea ostrearia was capable to inhibit the in vitro replication of HSV-1 in Vero cells with 50% inhibitory concentration (EC50) of 14 micrograms/ml at a multiplicity of infection of 0.01 ID50/cells. In addition, this fraction delayed the HIV-1-induced syncitia formation on MT4 cells. At concentrations up to 200 micrograms/ml, no cytotoxicity was observed for both the Vero and MT4 cells. The fraction only inhibited the blood coagulation process at concentrations considerably exceeding the EC50.
