Insights into substrate transport and water permeation in the mycobacterial transporter MmpL3.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
06 06 2023
06 06 2023
Historique:
received:
17
10
2022
revised:
04
02
2023
accepted:
10
03
2023
pmc-release:
06
06
2024
medline:
9
6
2023
pubmed:
18
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
Mycobacteria, such as Mycobacterium tuberculosis, are characterized by a uniquely thick and waxy cell envelope that consists of two membranes, with a variety of mycolates comprising their outer membrane (OM). The protein Mycobacterial membrane protein Large 3 (MmpL3) is responsible for the transport of a primary OM component, trehalose monomycolate (TMM), from the inner (cytoplasmic) membrane (IM) to the periplasmic space, a process driven by the proton gradient. Although multiple structures of MmpL3 with bound substrates have been solved, the exact pathway(s) for TMM or proton transport remains elusive. Here, employing molecular dynamics simulations we investigate putative pathways for either transport species. We hypothesized that MmpL3 will cycle through similar conformational states as the related transporter AcrB, which we used as targets for modeling the conformation of MmpL3. A continuous water pathway through the transmembrane region was found in one of these states, illustrating a putative pathway for protons. Additional equilibrium simulations revealed that TMM can diffuse from the membrane into a binding pocket in MmpL3 spontaneously. We also found that acetylation of TMM, which is required for transport, makes it more stable within MmpL3's periplasmic cavity compared with the unacetylated form.
Identifiants
pubmed: 36926696
pii: S0006-3495(23)00171-6
doi: 10.1016/j.bpj.2023.03.018
pmc: PMC10257117
pii:
doi:
Substances chimiques
Membrane Proteins
0
Protons
0
Bacterial Proteins
0
Membrane Transport Proteins
0
Carrier Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2342-2352Subventions
Organisme : NIAID NIH HHS
ID : R01 AI116525
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM104601
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM145965
Pays : United States
Informations de copyright
Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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