Nandan Haloi, Po-Chao Wen, Qunli Cheng, Meiying Yang, Gayathri Natarajan,
Amadou KS Camara, Wai-Meng Kwok, and Emad Tajkhorshid.
Structural basis of complex formation between mitochondrial anion
channel VDAC1 and hexokinase-II.
Communications Biology, 4:667, 2021.
HALO2021-ET
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.
