The Structural Basis for Low Conductance in the Membrane Protein VDAC upon β-NADH Binding and Voltage Gating.
NADH
NMR spectroscopy
VDAC gating
crosslinking
electrophysiology
membrane protein
molecular dynamics
protein dynamics
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
04 02 2020
04 02 2020
Historique:
received:
26
07
2019
revised:
27
09
2019
accepted:
26
11
2019
pubmed:
22
12
2019
medline:
30
4
2021
entrez:
22
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31862297
pii: S0969-2126(19)30433-2
doi: 10.1016/j.str.2019.11.015
pmc: PMC8353649
mid: NIHMS1723070
pii:
doi:
Substances chimiques
VDAC1 protein, human
0
NAD
0U46U6E8UK
Voltage-Dependent Anion Channel 1
EC 1.6.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
206-214.e4Subventions
Organisme : NIAID NIH HHS
ID : R01 AI150709
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM132079
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM129026
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB002026
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM075879
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM066360
Pays : United States
Organisme : NIH HHS
ID : S10 OD023513
Pays : United States
Organisme : NIGMS NIH HHS
ID : P01 GM055876
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare that they have no conflict of interest.
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