The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms b...The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.展开更多
Leptin receptor(LepR)signaling plays an essential role in balancing food intake and energy expenditure.The architec-ture of LepR signaling assembly is critical for its function.In this study,we determined the structur...Leptin receptor(LepR)signaling plays an essential role in balancing food intake and energy expenditure.The architec-ture of LepR signaling assembly is critical for its function.In this study,we determined the structures of three distinct conformations of human leptin–LepR using cryo-electron microscopy at resolutions of 3.88,3.77,and 3.58Å.Both 2:2 and 3:3 stoichiometric assemblies were observed,and the complexes exhibited asymmetric open conformations.Lep-tin undergoes substantial rearrangement of its flexible regions to accommodate binding to LepR.The assembled leptin–LepR complexes connect through a“hand-in-hand”geometry.The open,interlocked 3:3 trimeric assembly results from the engagement of a third leptin–LepR heterodimer with a 2:2 dimer.The asymmetric geometry of LepR is substantially distinct from that of other gp130 cytokine homologs,and that may be due to the twisted and rigid interface between the D3 and D4 domains.These results highlight the distinct engagement of leptin with LepR and provide important insights into the structural plasticity of LepR-signaling assemblies.展开更多
基金supported by grants from the National Key R&D Program of China(2021YFC2301400)the National Natural Science Foundation of China(32070876,82071155,82271023 and 82301052)the Shanxi Provincial Science Fund for Distinguished Young Scholars program(202103021221001 and 202303021223007).
文摘The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.
基金sup-ported by the National Key Research and Development Program of China (grant numbers 2020YFA0509202).
文摘Leptin receptor(LepR)signaling plays an essential role in balancing food intake and energy expenditure.The architec-ture of LepR signaling assembly is critical for its function.In this study,we determined the structures of three distinct conformations of human leptin–LepR using cryo-electron microscopy at resolutions of 3.88,3.77,and 3.58Å.Both 2:2 and 3:3 stoichiometric assemblies were observed,and the complexes exhibited asymmetric open conformations.Lep-tin undergoes substantial rearrangement of its flexible regions to accommodate binding to LepR.The assembled leptin–LepR complexes connect through a“hand-in-hand”geometry.The open,interlocked 3:3 trimeric assembly results from the engagement of a third leptin–LepR heterodimer with a 2:2 dimer.The asymmetric geometry of LepR is substantially distinct from that of other gp130 cytokine homologs,and that may be due to the twisted and rigid interface between the D3 and D4 domains.These results highlight the distinct engagement of leptin with LepR and provide important insights into the structural plasticity of LepR-signaling assemblies.
