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Dynamic interplay between a TonB-dependent heme transporter and a TonB protein in a membrane environment.
Dynamic interplay between a TonB-dependent heme transporter and a TonB protein in a membrane environment.
- Source :
-
MBio [mBio] 2024 Dec 11; Vol. 15 (12), pp. e0178124. Date of Electronic Publication: 2024 Oct 30. - Publication Year :
- 2024
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Abstract
- The envelope of Gram-negative bacteria is composed of two membranes separated by the periplasmic space. This organization imposes geometrical and distance constraints that are key for the mechanism of action of multicomponent systems spanning the envelope. However, consideration of all three compartments by experimental approaches is still elusive. Here, we have used the state-of-the-art molecular dynamics simulation in an Escherichia coli envelope model to obtain a dynamic view of molecular interactions between the outer membrane heme transporter HasR and the inner membrane TonB-like protein HasB. Their interaction allows the transfer of the inner membrane proton-motive force derived energy to the transporter for heme internalization. The simulations that incorporate both membranes show the key role of periplasmic domains of both proteins and their dynamics in complex formation and stability. They revealed a previously unidentified network of HasR-HasB protein-protein interactions in the periplasm. Experimental validation (mutations, in vivo phenotypic and biophysical assays) provides support for the simulation-predicted interactions. Based on structural and sequence conservation, the network of interaction revealed in this study is expected to occur in other nutrient import systems.<br />Importance: Gram-negative bacteria import scarce nutrients such as metals and vitamins by an energized mechanism involving a multicomponent protein system that spans the cell envelope. It consists of an outer membrane TonB-dependent transporter (TBDT) and a TonB complex in the inner membrane that provides the proton motive force energy for the nutrient entry. Despite the intense research efforts focused on this system (a) from structural and fundamental microbiology perspectives and (b) for the interest in the development of new antibacterial strategies, the molecular mechanism of the system is not at all well understood. The lack of understanding comes from incomplete structural data and the experimental difficulties of studying an inherently flexible multicomponent complex that resides within the heterogeneous environment of the double membrane bacterial cell envelope. To address these challenges and obtain a comprehensive view of the molecular interactions at atomic level, here, we have used the combined power of advanced molecular simulations and complementary microbiology and biochemical experiments. Our results represent a significant step forward in understanding the structural and molecular bases of this vital mechanism.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Membrane Transport Proteins metabolism
Membrane Transport Proteins genetics
Membrane Transport Proteins chemistry
Protein Binding
Cell Membrane metabolism
Periplasm metabolism
Bacterial Outer Membrane Proteins metabolism
Bacterial Outer Membrane Proteins genetics
Bacterial Outer Membrane Proteins chemistry
Bacterial Proteins
Escherichia coli Proteins metabolism
Escherichia coli Proteins genetics
Escherichia coli Proteins chemistry
Escherichia coli metabolism
Escherichia coli genetics
Membrane Proteins metabolism
Membrane Proteins genetics
Membrane Proteins chemistry
Molecular Dynamics Simulation
Heme metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2150-7511
- Volume :
- 15
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- MBio
- Publication Type :
- Academic Journal
- Accession number :
- 39475239
- Full Text :
- https://doi.org/10.1128/mbio.01781-24