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Structural basis of complex formation between mitochondrial anion channel VDAC1 and Hexokinase-II.
Haloi, Nandan; Wen, Po-Chao; Cheng, Qunli; Yang, Meiying; Natarajan, Gayathri; Camara, Amadou K S; Kwok, Wai-Meng; Tajkhorshid, Emad.
Afiliación
  • Haloi N; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Wen PC; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Cheng Q; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Yang M; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Natarajan G; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Camara AKS; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • Kwok WM; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Tajkhorshid E; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Commun Biol ; 4(1): 667, 2021 06 03.
Article en En | MEDLINE | ID: mdl-34083717
Complex formation between hexokinase-II (HKII) and the mitochondrial VDAC1 is crucial to cell growth and survival. We hypothesize that HKII first inserts into the outer membrane of mitochondria (OMM) and then interacts with VDAC1 on the cytosolic leaflet of OMM to form a binary complex. To systematically investigate this process, we devised a hybrid approach. First, we describe membrane binding of HKII with molecular dynamics (MD) simulations employing a membrane mimetic model with enhanced lipid diffusion capturing membrane insertion of its H-anchor. The insertion depth of the H-anchor was then used to derive positional restraints in subsequent millisecond-scale Brownian dynamics (BD) simulations to preserve the membrane-bound pose of HKII during the formation of the HKII/VDAC1 binary complex. Multiple BD-derived structural models for the complex were further refined and their structural stability probed with additional MD simulations, resulting in one stable complex. A major feature in the complex is the partial (not complete) blockade of VDAC1's permeation pathway, a result supported by our comparative electrophysiological measurements of the channel in the presence and absence of HKII. We also show how VDAC1 phosphorylation disrupts HKII binding, a feature that is verified by our electrophysiology recordings and has implications in mitochondria-mediated cell death.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Mitocondriales / Complejos Multiproteicos / Canal Aniónico 1 Dependiente del Voltaje / Simulación de Dinámica Molecular / Hexoquinasa Límite: Humans Idioma: En Revista: Commun Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Mitocondriales / Complejos Multiproteicos / Canal Aniónico 1 Dependiente del Voltaje / Simulación de Dinámica Molecular / Hexoquinasa Límite: Humans Idioma: En Revista: Commun Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido