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The Structural Basis for Low Conductance in the Membrane Protein VDAC upon β-NADH Binding and Voltage Gating.

Böhm R, Amodeo GF, Murlidaran S, Chavali S, Wagner G, Winterhalter M, Brannigan G, Hiller S
Structure 28 206-214.e4 (2020)
Cited: 19 times
EuropePMC logo PMID: 31862297

Abstract

The voltage-dependent anion channel (VDAC) forms the primary diffusion pore of the outer mitochondrial membrane. In its apo form, VDAC adopts an open conformation with high conductance. States of lower conductance can be induced by ligand binding or the application of voltage. Here, we clarify at the atomic level how β-NADH binding leads to a low-conductance state and characterize the role of the VDAC N-terminal helix in voltage gating. A high-resolution NMR structure of human VDAC-1 with bound NADH, combined with molecular dynamics simulation show that β-NADH binding reduces the pore conductance sterically without triggering a structural change. Electrophysiology recordings of crosslinked protein variants and NMR relaxation experiments probing different time scales show that increased helix dynamics is present in the open state and that motions of the N-terminal helices are involved in the VDAC voltage gating mechanism.

Reviews - 6tiq mentioned but not cited (2)

  1. Gating of β-Barrel Protein Pores, Porins, and Channels: An Old Problem with New Facets. Mayse LA, Movileanu L. Int J Mol Sci 24 12095 (2023)
  2. Mitochondrial DNA in cell death and inflammation. Heilig R, Lee J, Tait SWG. Biochem Soc Trans 51 457-472 (2023)

Articles - 6tiq mentioned but not cited (1)

  1. Structure, gating and interactions of the voltage-dependent anion channel. Najbauer EE, Becker S, Giller K, Zweckstetter M, Lange A, Steinem C, de Groot BL, Griesinger C, Andreas LB. Eur Biophys J 50 159-172 (2021)


Reviews citing this publication (4)

  1. The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease. Varughese JT, Buchanan SK, Pitt AS. Cells 10 1737 (2021)
  2. VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges. Heslop KA, Milesi V, Maldonado EN. Front Physiol 12 742839 (2021)
  3. A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake? Sander P, Gudermann T, Schredelseker J. Int J Mol Sci 22 (2021)
  4. Post-translational modifications and protein quality control of mitochondrial channels and transporters. Kadam A, Jadiya P, Tomar D. Front Cell Dev Biol 11 1196466 (2023)

Articles citing this publication (12)

  1. The intrinsically disordered N-terminus of the voltage-dependent anion channel. Preto J, Krimm I. PLoS Comput Biol 17 e1008750 (2021)
  2. Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance. Srivastava SR, Mahalakshmi R. J Biol Chem 295 14653-14665 (2020)
  3. VDAC Gating Thermodynamics, but Not Gating Kinetics, Are Virtually Temperature Independent. Queralt-Martín M, Hoogerheide DP, Noskov SY, Berezhkovskii AM, Rostovtseva TK, Bezrukov SM. Biophys J 119 2584-2592 (2020)
  4. A Deep Dive into VDAC1 Conformational Diversity Using All-Atom Simulations Provides New Insights into the Structural Origin of the Closed States. Preto J, Gorny H, Krimm I. Int J Mol Sci 23 1175 (2022)
  5. Combining nano-differential scanning fluorimetry and microscale thermophoresis to investigate VDAC1 interaction with small molecules. Gorny H, Mularoni A, Delcros JG, Freton C, Preto J, Krimm I. J Enzyme Inhib Med Chem 38 2121821 (2023)
  6. Molecular mechanism of thiamine pyrophosphate import into mitochondria: a molecular simulation study. Van Liefferinge F, Krammer EM, Waeytens J, Prévost M. J Comput Aided Mol Des 35 987-1007 (2021)
  7. Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells. Olivas-Aguirre M, Torres-López L, Pottosin I, Dobrovinskaya O. Int J Mol Sci 22 (2020)
  8. Predicting molecular mechanism of silymarin-potentiated diclofenac toxicity: Insight from in silico molecular docking. Boonyong C, Jianmongkol S. Toxicol Rep 11 339-345 (2023)
  9. Small molecules targeting the NADH-binding pocket of VDAC modulate mitochondrial metabolism in hepatocarcinoma cells. Heslop KA, Burger P, Kappler C, Solanki AK, Gooz M, Peterson YK, Mills C, Benton T, Duncan SA, Woster PM, Maldonado EN. Biomed Pharmacother 150 112928 (2022)
  10. Structure and Gating Behavior of the Human Integral Membrane Protein VDAC1 in a Lipid Bilayer. Najbauer EE, Tekwani Movellan K, Giller K, Benz R, Becker S, Griesinger C, Andreas LB. J Am Chem Soc 144 2953-2967 (2022)
  11. Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival. Ventura C, Junco M, Santiago Valtierra FX, Gooz M, Zhiwei Y, Townsend DM, Woster PM, Maldonado EN. Eur J Pharmacol 957 176034 (2023)
  12. Two conformations of the Tom20 preprotein receptor in the TOM holo complex. Ornelas P, Bausewein T, Martin J, Morgner N, Nussberger S, Kühlbrandt W. Proc Natl Acad Sci U S A 120 e2301447120 (2023)


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