The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel1. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.

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ABCG2 is an ATP-binding cassette (ABC) transporter that extrudes a wide range of xenobiotics and drugs from the cell and contributes to multidrug resistance in cancer cells. Following our recent structural characterization of topotecan-bound ABCG2, here, we present cryo-EM structures of ABCG2 under turnover conditions in complex with a special modulator and slow substrate, tariquidar, in nanodiscs. The structures reveal that similar to topotecan, tariquidar induces two distinct ABCG2 conformations under turnover conditions (turnover-1 and turnover-2). μs-scale molecular dynamics simulations of drug-bound and apo ABCG2 in native-like lipid bilayers, in both topotecan- and tariquidar-bound states, characterize the ligand size as a major determinant of its binding stability. The simulations highlight direct lipid-drug interactions for the smaller topotecan, which exhibits a highly dynamic binding mode. In contrast, the larger tariquidar occupies most of the available volume in the binding pocket, thus leaving little space for lipids to enter the cavity and interact with it. Similarly, when simulating ABCG2 in the apo inward-open state, we also observe spontaneous penetration of phospholipids into the binding cavity. The captured phospholipid diffusion pathway into ABCG2 offers a putative general path to recruit any hydrophobic/amphiphilic substrates directly from the membrane. Our simulations also reveal that ABCG2 rejects cholesterol as a substrate, which is omnipresent in plasma membranes that contain ABCG2. At the same time, cholesterol is found to prohibit the penetration of phospholipids into ABCG2. These molecular findings have direct functional ramifications on ABCG2’s function as a transporter.

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Being in vicinity of vast deserts, the west and southwest of Iran are characterized by high levels of dust events, which have adverse consequences on human health, ecosystems, and environment. Using ground based dataset of dust events in western Iran and NCEP/NCAR reanalysis data, the atmospheric circulation patterns of dust events in the Arabian region and west of Iran are identified. The atmospheric circulation patterns which lead to dust events in the Arabian region and western Iran were classified into two main categories: the Shamal dust events that occurs in warm period of year and the frontal dust events as cold period pattern. In frontal dust events, the western trough or blocking pattern at mid-level leads to frontogenesis, instability, and air uplift at lower levels of troposphere in the southwest of Asia. Non-frontal is other pattern of dust event in the cold period and dust generation are due to the regional circulation systems at the lower level of troposphere. In Shamal wind pattern, the Saudi Arabian anticyclone, Turkmenistan anticyclone, and Zagros thermal low play the key roles in formation of this pattern. Summer and transitional patterns are two sub-categories of summer Shamal wind pattern. In summer trough pattern, the mid-tropospheric trough leads to intensify the surface thermal systems in the Middle East and causes instability and rising of wind speed in the region. In synthetic pattern of Shamal wind and summer trough, dust is created by the impact of a trough in mid-levels of troposphere as well as existing the mentioned regional systems which are contributed in formation of summer Shamal wind pattern.