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Cryo-electron microscopy mapping of the calcium-activated chloride channel TMEM16A combined with functional experiments reveals that calcium ions interact directly with the pore to activate the channel.

The binding of cytoplasmic Ca²⁺ to the anion-selective channel TMEM16A triggers a conformational change around its binding site that is coupled to the release of a gate at the constricted neck. Here authors use cryo-EM and electrophysiology to identify three hydrophobic residues at the intracellular entrance of the neck as constituents of this gate.

The Tweety homologue TTYH2 is identified as the lipid transfer mediator for APOE-containing lipoproteins.

IST2 serves as a tether between the endoplasmic reticulum and the plasma membrane in yeast. Here, Arndt et al. interrogate its interaction with OSH6, revealing that the two proteins remain associated during lipid shuttling.

Iron and manganese are essential nutrients that have to be taken up with our diet and distributed in the body. This work describes the structural basis for the transport of these metal ions across membranes by the human transporters DMT1 and NRAMP1.

The anion channel TMEM16A is activated by intracellular Ca²⁺ in a highly cooperative process. Here authors combine electrophysiology and autocorrelation analysis to observe the sampling of intermediate conformations during gating.

TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is implicated in various diseases, but its pharmacology remains poorly understood. Here, the authors combine cryo-EM and electrophysiology to elucidate the mechanism of TMEM16A inhibition by the pore blocker 1PBC.

The human Tweety homologue (TTYH) family of transmembrane proteins have been suggested to act as chloride channels. Here the authors present cryo-EM structures of the 3 human TTYH paralogs that do not display the expected features of an anion channel, and instead appear to interact with lipid-like compounds residing in the membrane; suggesting an involvement in lipid-associated processes.

The authors describe the structure of a Ca²⁺-activated lipid scramblase which catalyses the passive movement of lipids between the two leaflets of a lipid bilayer; the structure reveals the location of a regulatory calcium-binding site embedded within the membrane and the presence of a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer, where catalysis is likely to occur.

The structure of a heteromeric volume-regulated LRRC8A/C channel shows a hexameric assembly of four clustered A subunits interspersed by two C subunits, which increase the mobility of the protein, thus facilitating channel activation.

TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.

The X-ray structure of a prokaryotic pentameric ligand-gated ion channels (pLGIC) from the bacterium Erwinia chrysanthemi (ELIC) at 3.3 Å resolution is presented. This study reveals the first structure of a pLGIC at high resolution and provides an important model system for the investigation of the general mechanisms of ion permeation and gating within the family.

Recently, the first crystal structure of a pentameric ligand-gated ion channel known as GLIC was published, which represented a closed state of the channel. In two papers in this issue, presumptive open states of a related channel — ELIC — have been crystallized and show significant tilting of the M2 and M3 α-helices from the closed state.

Volume-regulated anion channels (VRACs) are heteromers of LRRC8 proteins, all containing the obligatory subunit LRRC8A. Here, the authors develop and characterize nanobodies that bind LRRC8A and allosterically modulate the function of homomeric LRRC8A and endogenous heteromeric channels, hinting at functional mechanisms present in VRACs.

Cellular uptake of transition metal ions is mediated by members of the SLC11/NRAMP family. Here the authors determine the structural and functional properties of EcoDMT, a bacterial SLC11 transporter, gathering molecular insight into its transport mechanism and proton coupling process.

Open channel blockers are very different in their chemistry and structure. Now GLIC, a bacterial model for pentameric ligand-gated channels, is used to investigate the structural basis of open channel block. The work identifies two extended interaction sites, with large blockers binding to the center of the membrane and small blockers binding to the narrow intracellular region.

The structure of a homomeric channel of subunit A of leucine-rich repeat-containing protein 8 (LRRC8) determined by cryo-electron microscopy and X-ray crystallography reveals the basis for anion selectivity.

The X-ray crystal structure of ScaDMT, a bacterial member of the solute carrier 11 transporter family, identifies conserved residues within the substrate-binding site that confer metal-ion selectivity.

SLC26 membrane proteins constitute a large family of anion transporters with diverse functions. The first structure of a full-length SLC26 transporter now provides a common framework for the architecture of this protein family.