The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. The apo-form structure reveals two potential Na+ binding sites within the selectivity filter, suggesting a possible mechanism for Na+ selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na+ binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into NaV1.6 structure, ion conductance, and inhibition.
Abstract Salt-overly-sensitive 1 (SOS1) is a unique electroneutral Na + /H + antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. SOS1 is kept in a resting state with basal activity and activated upon phosphorylation. Here, we report the structures of SOS1. SOS1 forms a homodimer, with each monomer composed of transmembrane and intracellular domains. We find that SOS1 is locked in an occluded state by shifting of the lateral-gate TM5b toward the dimerization domain, thus shielding the Na + /H + binding site. We speculate that the dimerization of the intracellular domain is crucial to stabilize the transporter in this specific conformation. Moreover, two discrete fragments and a residue W1013 are important to prevent the transition of SOS1 to an alternative conformational state, as validated by functional complementation assays. Our study enriches understanding of the alternate access model of eukaryotic Na + /H + exchangers.
This study focuses on the close association between Devonian reefs and the strata-bound ore deposits in South China. For the first time, the development of Devonian reefs was subdivided into three stages, respectively as the initial, succeeding and peak stages, and its evolution model is proposed. In Dachang, Nandan county, Guangxi Zhuang Autonomous Region (Guangxi for short), a large-scale strata-bound ore deposit formed in a Devonian reef, which was affected by marine volcanic activities and Mesozoic magmatic intrusions. The reef-building reached its peak stage at the Givetian, indicating a large-scale build-up of reef and inter-reef depression. In central–eastern Hunan Province, the strata-bound ore deposits belong to low-temperature ore-types without later magmatic intrusions or volcanic activities. In Hunan Province as well as many other localities in South China, the Givetian reefs played important roles in mobilizing ore-forming materials from the surrounding pre-Devonian rocks, providing spaces and passages for transporting hydrothermal fluid, and progressing mineralization and accumulation of ore-forming materials.
Abstract With severe soil and water erosion, the crucial ion-adsorption rare earth elements (REEs) have attracted much global attention. REEs play a vital role in tracing material sources and exploring sedimentary characteristics due to their unique and stable geochemistry properties. In the present work, three representational possible redeposition areas in western Fujian were selected as the study areas. The geochemical characteristics of REEs in the sediments of the study areas were evaluated to elucidate that REEs are the products of soil and water erosion and to assess their redeposition characteristics. The results of the geochemical analysis indicated that the parent rocks of the study areas are primarily upper continental felsic rocks with similar geochemical characteristics, and the sediments in the study areas are the products of migration and redeposition caused by soil and water erosion. Moreover, the statistical analysis highlighted a negative correlation between REEs and elevation as well as REEs and the relief degree on the land surface (RDLS). Thus, as a result of soil and water erosion, ion-adsorption REEs in the surface sediments migrate and redeposit in the soil and water of the downstream redeposition areas. This leads to a high re-utilization potential of REEs in the current situation of scarcity of such resources.
Early Ordovician (late Tremadocian to early Floian) reefs on the Yangtze Platform margin of the Hunghuayuan Formation at Zhangzhai section in southeastern Guizhou, South China show three types of reefs in two broad categories: microbial-dominated (stromatolite and lithistid sponge-Calathium-calcimicrobial) reefs and metazoan-dominated (lithistid sponge-Calathium) reefs. These reef types represent different communities controlled by varying environmental settings. Stromatolites tended to develop in the shallow subtidal zone, whereas unlaminated calcimicrobial mounds and metazoan-dominated reefs thrived at greater depths. This is the first report on metazoan-dominated reefs at the platform margin of the Hunghuayuan Formation.
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