Structural basis of complex formation between mitochondrial anion channel VDAC1 and Hexokinase-II

Commun Biol. 2021 Jun 3;4(1):667. doi: 10.1038/s42003-021-02205-y.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Hexokinase / chemistry
  • Hexokinase / genetics
  • Hexokinase / metabolism*
  • Humans
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Dynamics Simulation*
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Protein Binding
  • Protein Domains
  • Voltage-Dependent Anion Channel 1 / chemistry
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism*

Substances

  • Mitochondrial Proteins
  • Multiprotein Complexes
  • VDAC1 protein, human
  • Voltage-Dependent Anion Channel 1
  • Hexokinase

Associated data

  • figshare/10.6084/m9.figshare.14511885