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Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A

Kuznetsova, Anastasiya and Masrati, Gal and Vigonsky, Elena and Livnat-Levanon, Nurit and Rose, Jessica and Grupper, Moti and Baloum, Adan and Yang, Janet G. and Rees, Douglas C. and Ben-Tal, Nir and Lewinson, Oded (2021) Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A. Journal of Biological Chemistry, 297 (4). Art. No. 101087. ISSN 0021-9258. doi:10.1016/j.jbc.2021.101087. https://resolver.caltech.edu/CaltechAUTHORS:20210908-171144390

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Abstract

All extant life forms require trace transition metals (e.g., Fe^(2/3+), Cu^(1/2+), and Mn^(2+)) to survive. However, as these are environmentally scarce, organisms have evolved sophisticated metal uptake machineries. In bacteria, high-affinity import of transition metals is predominantly mediated by ABC transporters. During bacterial infection, sequestration of metal by the host further limits the availability of these ions, and accordingly, bacterial ABC transporters (importers) of metals are key virulence determinants. However, the structure–function relationships of these metal transporters have not been fully elucidated. Here, we used metal-sensitivity assays, advanced structural modeling, and enzymatic assays to study the ABC transporter MntBC-A, a virulence determinant of the bacterial human pathogen Bacillus anthracis. We find that despite its broad metal-recognition profile, MntBC-A imports only manganese, whereas zinc can function as a high-affinity inhibitor of MntBC-A. Computational analysis shows that the transmembrane metal permeation pathway is lined with six titratable residues that can coordinate the positively charged metal, and mutagenesis studies show that they are essential for manganese transport. Modeling suggests that access to these titratable residues is blocked by a ladder of hydrophobic residues, and ATP-driven conformational changes open and close this hydrophobic seal to permit metal binding and release. The conservation of this arrangement of titratable and hydrophobic residues among ABC transporters of transition metals suggests a common mechanism. These findings advance our understanding of transmembrane metal recognition and permeation and may aid the design and development of novel antibacterial agents.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.jbc.2021.101087DOIArticle
ORCID:
AuthorORCID
Masrati, Gal0000-0003-1322-5762
Yang, Janet G.0000-0002-5619-9544
Rees, Douglas C.0000-0003-4073-1185
Ben-Tal, Nir0000-0001-6901-832X
Lewinson, Oded0000-0003-4650-0441
Additional Information:© 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 9 February 2021, Revised 12 August 2021, Accepted 16 August 2021, Available online 18 August 2021. This work was supported by grants from the NATO Science for Peace and Security Program (SPS 625 Project G4622, to O. L. and N. B.-T.), the US-Israel Binational Science Foundation (BSF grant 2015102 to O. L. and D. C. R.), and the Israel Academy of Sciences and Humanities project 1006/18 (to O. L.). Data availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Author contributions: A. K., E. V., N. L.-L., J. R., M. G., A. B., and O. L. investigation; A. K., J. R., M. G., A. B., and O. L. visualization; G. M. data curation; G. M. formal analysis; G. M., E. V., N. L.-L., and O. L. methodology; N. L.-L., J. G. Y., D. C. R., N. B.-T., and O. L. supervision; J. G. Y., D. C. R., N. B.-T., and O. L. project administration; D. C. R., N. B.-T., and O. L. funding acquisition; O. L. conceptualization; O. L. and N. B.-T. validation; O. L. writing–original draft; O. L. and N. B.-T. writing–review and editing. The authors declare that they have no conflicts of interest with the contents of this article.
Funders:
Funding AgencyGrant Number
North Atlantic Treaty Organization (NATO)SPS 625 Project G4622
Binational Science Foundation (USA-Israel)2015102
Israeli Academy of Sciences1006/18
Subject Keywords:ABC transporter; virulence; transition metals; metal binding; membrane proteins; ATPase
Issue or Number:4
DOI:10.1016/j.jbc.2021.101087
Record Number:CaltechAUTHORS:20210908-171144390
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210908-171144390
Official Citation:Anastasiya Kuznetsova, Gal Masrati, Elena Vigonsky, Nurit Livnat-Levanon, Jessica Rose, Moti Grupper, Adan Baloum, Janet G. Yang, Douglas C. Rees, Nir Ben-Tal, Oded Lewinson, Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A, Journal of Biological Chemistry, Volume 297, Issue 4, 2021, 101087, ISSN 0021-9258, https://doi.org/10.1016/j.jbc.2021.101087. (https://www.sciencedirect.com/science/article/pii/S0021925821008905)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110783
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Sep 2021 17:51
Last Modified:04 Oct 2021 20:25

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