Multiple neurosteroid and cholesterol binding sites in voltage-dependent anion channel-1 determined by photo-affinity labeling.
Cholesterol
Mass spectrometry
Neurosteroid
Photoaffinity labeling
Protein drug interaction
Voltage-dependent anion channel (VDAC)
Journal
Biochimica et biophysica acta. Molecular and cell biology of lipids
ISSN: 1879-2618
Titre abrégé: Biochim Biophys Acta Mol Cell Biol Lipids
Pays: Netherlands
ID NLM: 101731727
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
18
02
2019
revised:
23
05
2019
accepted:
02
06
2019
pubmed:
9
6
2019
medline:
7
3
2020
entrez:
9
6
2019
Statut:
ppublish
Résumé
Voltage-dependent anion channel-1 (VDAC1) is a mitochondrial porin that is implicated in cellular metabolism and apoptosis, and modulated by numerous small molecules including lipids. VDAC1 binds sterols, including cholesterol and neurosteroids such as allopregnanolone. Biochemical and computational studies suggest that VDAC1 binds multiple cholesterol molecules, but photolabeling studies have identified only a single cholesterol and neurosteroid binding site at E73. To identify all the binding sites of neurosteroids in VDAC1, we apply photo-affinity labeling using two sterol-based photolabeling reagents with complementary photochemistry: 5α-6-AziP which contains an aliphatic diazirine, and KK200 which contains a trifluoromethyl-phenyldiazirine (TPD) group. 5α-6-AziP and KK200 photolabel multiple residues within an E73 pocket confirming the presence of this site and mapping sterol orientation within this pocket. In addition, KK200 photolabels four other sites consistent with the finding that VDAC1 co-purifies with five cholesterol molecules. Both allopregnanolone and cholesterol competitively prevent photolabeling at E73 and three other sites indicating that these are common sterol binding sites shared by both neurosteroids and cholesterol. Binding at the functionally important residue E73 suggests a possible role for sterols in regulating VDAC1 signaling and interaction with partner proteins.
Identifiants
pubmed: 31176038
pii: S1388-1981(19)30096-4
doi: 10.1016/j.bbalip.2019.06.004
pmc: PMC6681461
mid: NIHMS1041671
pii:
doi:
Substances chimiques
Neurosteroids
0
Vdac1 protein, mouse
0
Cholesterol
97C5T2UQ7J
Voltage-Dependent Anion Channel 1
EC 1.6.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1269-1279Subventions
Organisme : NIGMS NIH HHS
ID : K08 GM126336
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM108539
Pays : United States
Organisme : NIGMS NIH HHS
ID : P01 GM047969
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM078844
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM108799
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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