Project description:Languages are transmitted through channels created by kinship systems. Given sufficient time, these kinship channels can change the genetic and linguistic structure of populations. In traditional societies of eastern Indonesia, finely resolved cophylogenies of languages and genes reveal persistent movements between stable speech communities facilitated by kinship rules. When multiple languages are present in a region and postmarital residence rules encourage sustained directional movement between speech communities, then languages should be channeled along uniparental lines. We find strong evidence for this pattern in 982 individuals from 25 villages on two adjacent islands, where different kinship rules have been followed. Core groups of close relatives have stayed together for generations, while remaining in contact with, and marrying into, surrounding groups. Over time, these kinship systems shaped their gene and language phylogenies: Consistently following a postmarital residence rule turned social communities into speech communities.
Project description:Potassium channels are present in every living cell and essential to setting up a stable, non-zero transmembrane electrostatic potential which manifests the off-equilibrium livelihood of the cell. They are involved in other cellular activities and regulation, such as the controlled release of hormones, the activation of T-cells for immune response, the firing of action potential in muscle cells and neurons, etc. Pharmacological reagents targeting potassium channels are important for treating various human diseases linked to dysfunction of the channels. High-resolution structures of these channels are very useful tools for delineating the detailed chemical basis underlying channel functions and for structure-based design and optimization of their pharmacological and pharmaceutical agents. Structural studies of potassium channels have revolutionized biophysical understandings of key concepts in the field - ion selectivity, conduction, channel gating, and modulation, making them multi-modality targets of pharmacological regulation. In this chapter, I will select a few high-resolution structures to illustrate key structural insights, proposed allostery behind channel functions, disagreements still open to debate, and channel-lipid interactions and co-evolution. The known structural consensus allows the inference of conserved molecular mechanisms shared among subfamilies of K+ channels and makes it possible to develop channel-specific pharmaceutical agents.
Project description:Electron cryotomography (ECT) can reveal the native structure and arrangement of macromolecular complexes inside intact cells. This technique has greatly advanced our understanding of the ultrastructure of bacterial cells. We now view bacteria as structurally complex assemblies of macromolecular machines rather than as undifferentiated bags of enzymes. To date, our group has applied ECT to nearly 90 different bacterial species, collecting more than 15,000 cryotomograms. In addition to known structures, we have observed, to our knowledge, several uncharacterized features in these tomograms. Some are completely novel structures; others expand the features or species range of known structure types. Here, we present a survey of these uncharacterized bacterial structures in the hopes of accelerating their identification and study, and furthering our understanding of the structural complexity of bacterial cells.IMPORTANCE Bacteria are more structurally complex than is commonly appreciated. Here we present a survey of previously uncharacterized structures that we observed in bacterial cells by electron cryotomography, structures that will initiate new lines of research investigating their identities and roles.
Project description:Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca(2+) signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ∼85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca(2+)-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.
Project description:Novel structures of the human TRPA1 channel were determined in the presence of the agonist iodoacetamide and the antagonist A-967079, to reveal the open and closed states of the channel, respectively. The structures further revealed the location of Ca2+ modulatory site that is likely conserved among several TRP subgroups.
Project description:Bestrophin-1 (Best1) and bestrophin-2 (Best2) are two members of the bestrophin family of calcium (Ca2+)-activated chloride (Cl-) channels with critical involvement in ocular physiology and direct pathological relevance. Here, we report cryo-EM structures of wild-type human Best1 and Best2 in various states at up to 1.8 Å resolution. Ca2+-bound Best1 structures illustrate partially open conformations at the two Ca2+-dependent gates of the channels, in contrast to the fully open conformations observed in Ca2+-bound Best2, which is in accord with the significantly smaller currents conducted by Best1 in electrophysiological recordings. Comparison of the closed and open states reveals a C-terminal auto-inhibitory segment (AS), which constricts the channel concentrically by wrapping around the channel periphery in an inter-protomer manner and must be released to allow channel opening. Our results demonstrate that removing the AS from Best1 and Best2 results in truncation mutants with similar activities, while swapping the AS between Best1 and Best2 results in chimeric mutants with swapped activities, underlying a key role of the AS in determining paralog specificity among bestrophins.
Project description:Otopetrins (Otop1-Otop3) comprise one of two known eukaryotic proton-selective channel families. Otop1 is required for otoconia formation and a candidate mammalian sour taste receptor. Here we report cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture, with each subunit forming 12 transmembrane helices divided into structurally similar amino (N) and carboxy (C) domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a central tunnel. In molecular dynamics simulations, hydrophilic vestibules formed by the N and C domains and in the intrasubunit interface between N and C domains form conduits for water entry into the membrane core, suggesting three potential proton conduction pathways. By mutagenesis, we tested the roles of charged residues in each putative permeation pathway. Our results provide a structural basis for understanding selective proton permeation and gating of this conserved family of proton channels.
Project description:MgtE is a Mg 2+-selective channel regulated by the intracellular Mg 2+ concentration. MgtE family proteins are highly conserved in all domains of life and contribute to cellular Mg 2+ homeostasis. In humans, mutations in the SLC41 proteins, the eukaryotic counterparts of the bacterial MgtE, are known to be associated with various diseases. The first MgtE structure from a thermophilic bacterium, Thermus thermophilus, revealed that MgtE forms a homodimer consisting of transmembrane and cytoplasmic domains with a plug helix connecting the two and that the cytoplasmic domain possesses multiple Mg 2+ binding sites. Structural and electrophysiological analyses revealed that the dissociation of Mg 2+ ions from the cytoplasmic domain induces structural changes in the cytoplasmic domain, leading to channel opening. Thus, previous works showed the importance of MgtE cytoplasmic Mg 2+ binding sites. Nevertheless, due to the limited structural information on MgtE from different species, the conservation and diversity of the cytoplasmic Mg 2+ binding site in MgtE family proteins remain unclear. Here, we report crystal structures of the Mg 2+-bound MgtE cytoplasmic domains from two different bacterial species, Chryseobacterium hispalense and Clostridiales bacterium, and identify multiple Mg 2+ binding sites, including ones that were not observed in the previous MgtE structure. These structures reveal the conservation and diversity of the cytoplasmic Mg 2+ binding site in the MgtE family proteins.
Project description:Potassium channels are responsible for the selective yet efficient permeation of potassium ions across cell membranes. Despite many available high-resolution structures of potassium channels, those conformations inform only on static information on the ion permeation processes. Here, we use molecular dynamics simulations and Markov state models to obtain dynamical details of ion permeation. The permeation cycles, expressed in terms of selectivity filter occupancy and representing ion permeation events, are illustrated. We show that the direct knock-on permeation represents the dominant permeation mechanism over a wide range of potassium concentrations, temperatures, and membrane voltages for the pore of MthK. Direct knock-on is also observed in other potassium channels with a highly conserved selectivity filter, demonstrating the robustness of the permeation mechanism. Lastly, we investigate the charge strength dependence of permeation cycles. Our results shed light on the underlying permeation details, which are valuable in studying conduction mechanisms in potassium channels.