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Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides (2021)

Sung, Min Woo ; Yang, Zhongying ; Driggers, Camden M. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2109441118. Published 2021 Oct 28. doi: 10.1073/pnas.2109441118.

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Publikationsdatum: 2021-10-28

Beschreibung: Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined cryogenic electron microscopy structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational “propeller” and “quatrefoil” geometries surrounding their Kir6.1 core. The glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B, and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated, and MgADP-bound activated conformations wherein the glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.

Print ISSN: 0027-8424

Digitale ISSN: 1091-6490

Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Calcineurin regulates the stability and activity of estrogen receptor α (2021)

Masaki, Takahiro ; Habara, Makoto ; Sato, Yuki ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2114258118. Published 2021 Oct 28. doi: 10.1073/pnas.2114258118.

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Publikationsdatum: 2021-10-28

Beschreibung: Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Empirical audit and review and an assessment of evidentiary value in research on the psychological consequences of scarcity (2021)

O’Donnell, Michael ; Dev, Amelia S. ; Antonoplis, Stephen ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2103313118. Published 2021 Oct 28. doi: 10.1073/pnas.2103313118.

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Beschreibung: Empirical audit and review is an approach to assessing the evidentiary value of a research area. It involves identifying a topic and selecting a cross-section of studies for replication. We apply the method to research on the psychological consequences of scarcity. Starting with the papers citing a seminal publication in the field, we conducted replications of 20 studies that evaluate the role of scarcity priming in pain sensitivity, resource allocation, materialism, and many other domains. There was considerable variability in the replicability, with some strong successes and other undeniable failures. Empirical audit and review does not attempt to assign an overall replication rate for a heterogeneous field, but rather facilitates researchers seeking to incorporate strength of evidence as they refine theories and plan new investigations in the research area. This method allows for an integration of qualitative and quantitative approaches to review and enables the growth of a cumulative science.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Double peroxidase and histone acetyltransferase AgTip60 maintain innate immune memory in primed mosquitoes (2021)

Gomes, Fabio M. ; Tyner, Miles D. W. ; Barletta, Ana Beatriz F. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2114242118. Published 2021 Oct 28. doi: 10.1073/pnas.2114242118.

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Publikationsdatum: 2021-10-28

Beschreibung: Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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First-order antiferromagnetic transitions of SrMn2P2 and CaMn2P2 single crystals containing corrugated-honeycomb Mn sublattices (2021)

Sangeetha, N. S. ; Pakhira, Santanu ; Ding, Qing-Ping ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2108724118. Published 2021 Oct 28. doi: 10.1073/pnas.2108724118.

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Publikationsdatum: 2021-10-28

Beschreibung: SrMn2P2 and CaMn2P2 are insulators that adopt the trigonal CaAl2Si2-type structure containing corrugated Mn honeycomb layers. Magnetic susceptibility χ and heat capacity versus temperature T data reveal a weak first-order antiferromagnetic (AFM) transition at the Néel temperature TN=53(1) K for SrMn2P2 and a strong first-order AFM transition at TN=69.8(3) K for CaMn2P2. Both compounds exhibit isotropic and nearly T-independent χ(T≤TN), suggesting magnetic structures in which nearest-neighbor moments are aligned at ≈120° to each other. The 31P NMR measurements confirm the strong first-order transition in CaMn2P2 but show critical slowing down above TN for SrMn2P2, thus also evidencing second-order character. The 31P NMR measurements indicate that the AFM structure of CaMn2P2 is commensurate with the lattice whereas that of SrMn2P2 is incommensurate. These first-order AFM transitions are unique among the class of (Ca, Sr, Ba)Mn2 (P, As, Sb, Bi)2 compounds that otherwise exhibit second-order AFM transitions. This result challenges our understanding of the circumstances under which first-order AFM transitions occur.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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Strong π-stacking causes unusually large anisotropic thermal expansion and thermochromism (2021)

Dharmarwardana, Madushani ; Otten, Brooke M. ; Ghimire, Mukunda M. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2106572118. Published 2021 Oct 27. doi: 10.1073/pnas.2106572118.

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Publikationsdatum: 2021-10-27

Beschreibung: π-stacking in ground-state dimers/trimers/tetramers of N-butoxyphenyl(naphthalene)diimide (BNDI) exceeds 50 kcal ⋅ mol−1 in strength, drastically surpassing that for the *3[pyrene]2 excimer (∼30 kcal ⋅ mol−1; formal bond order = 1) and similar to other weak-to-moderate classical covalent bonds. Cooperative π-stacking in triclinic (BNDI-T) and monoclinic (BNDI-M) polymorphs effects unusually large linear thermal expansion coefficients (αa, αb, αc, β) of (452, −16.8, −154, 273) × 10−6 ⋅ K−1 and (70.1, −44.7, 163, 177) × 10−6 ⋅ K−1, respectively. BNDI-T exhibits highly reversible thermochromism over a 300-K range, manifest by color changes from orange (ambient temperature) toward red (cryogenic temperatures) or yellow (375 K), with repeated thermal cycling sustained for over at least 2 y.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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Retraction for Nojiri et al., Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells (2021)

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2117617118. Published 2021 Oct 27. doi: 10.1073/pnas.2117617118.

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Publikationsdatum: 2021-10-27

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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Cryo-EM structure of the needle filament tip complex of the Salmonella type III secretion injectisome (2021)

Guo, Emily Z. ; Galán, Jorge E.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2114552118. Published 2021 Oct 27. doi: 10.1073/pnas.2114552118.

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Publikationsdatum: 2021-10-27

Beschreibung: Type III secretion systems are multiprotein molecular machines required for the virulence of several important bacterial pathogens. The central element of these machines is the injectisome, a ∼5-Md multiprotein structure that mediates the delivery of bacterially encoded proteins into eukaryotic target cells. The injectisome is composed of a cytoplasmic sorting platform, and a membrane-embedded needle complex, which is made up of a multiring base and a needle-like filament that extends several nanometers from the bacterial surface. The needle filament is capped at its distal end by another substructure known as the tip complex, which is crucial for the translocation of effector proteins through the eukaryotic cell plasma membrane. Here we report the cryo-EM structure of the Salmonella Typhimurium needle tip complex docked onto the needle filament tip. Combined with a detailed analysis of structurally guided mutants, this study provides major insight into the assembly and function of this essential component of the type III secretion protein injection machine.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

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Berry curvature generation detected by Nernst responses in ferroelectric Weyl semimetal (2021)

Zhang, Cheng-Long ; Liang, Tian ; Bahramy, M. S. ; [weitere]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(44): e2111855118. Published 2021 Oct 27. doi: 10.1073/pnas.2111855118.

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Publikationsdatum: 2021-10-27

Beschreibung: The quest for nonmagnetic Weyl semimetals with high tunability of phase has remained a demanding challenge. As the symmetry-breaking control parameter, the ferroelectric order can be steered to turn on/off the Weyl semimetals phase, adjust the band structures around the Fermi level, and enlarge/shrink the momentum separation of Weyl nodes which generate the Berry curvature as the emergent magnetic field. Here, we report the realization of a ferroelectric nonmagnetic Weyl semimetal based on indium-doped Pb1−xSnxTe alloy in which the underlying inversion symmetry as well as mirror symmetry are broken with the strength of ferroelectricity adjustable via tuning the indium doping level and Sn/Pb ratio. The transverse thermoelectric effect (i.e., Nernst effect), both for out-of-plane and in-plane magnetic field geometry, is exploited as a Berry curvature–sensitive experimental probe to manifest the generation of Berry curvature via the redistribution of Weyl nodes under magnetic fields. The results demonstrate a clean, nonmagnetic Weyl semimetal coupled with highly tunable ferroelectric order, providing an ideal platform for manipulating the Weyl fermions in nonmagnetic systems.

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Thema: Biologie , Medizin , Allgemeine Naturwissenschaft

Publiziert von National Academy of Sciences

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