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Sökning: WFRF:(Mim Carsten) > (2020)

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  • Gowrisankaran, Sindhuja, et al. (författare)
  • Cells Control BIN1-Mediated Membrane Tubulation by Altering the Membrane Charge
  • 2020
  • Ingår i: Journal of Molecular Biology. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 0022-2836 .- 1089-8638. ; 432:4, s. 1235-1250
  • Tidskriftsartikel (refereegranskat)abstract
    • The Bridging integrator 1 (BIN1)/Amphiphysin/Rvs (BAR) protein family is an essential part of the cell's machinery to bend membranes. BIN1 is a muscle-enriched BAR protein with an established role in muscle development and skeletal myopathies. Here, we demonstrate that BIN1, on its own, is able to form complex interconnected tubular systems in vitro, reminiscent of t-tubule system in muscle cells. We further describe how BIN1's electrostatic interactions regulate membrane bending: the ratio of negatively charged lipids in the bilayer altered membrane bending and binding properties of BIN1 and so did the manipulation of BIN1's surface charge. We show that the electrostatically mediated BIN1 membrane binding depended on the membrane curvature-it was less affected in liposomes with high curvature. Curiously, BIN1 membrane binding and bending was diminished in cells where the membrane's charge was experimentally reduced. Membrane bending was also reduced in BIN1 mutants where negative or positive charges in the BAR domain have been eliminated. This phenotype, characteristic of BIN1 mutants linked to myopathies, was rescued when the membrane charge was made more negative. The latter findings also show that cells can control tubulation at their membranes by simply altering the membrane charge and through it, the recruitment of BAR proteins and their interaction partners (e.g. dynamin).
  • Sporny, Michael, et al. (författare)
  • Structural basis for SARM1 inhibition and activation under energetic stress
  • 2020
  • Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 angstrom resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.
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  • Resultat 1-2 av 2

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