Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i>
<i>Background and Objective</i>: ATP-binding cassette (ABC) transporters are prominent drug targets due to their highly efficient trafficking capabilities and their significant physiological and clinical roles. Gaining insight into their biophysical and biomechanistic properties is cruci...
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2024-11-01
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| author | Aisha Farhana Abdullah Alsrhani Hasan Ejaz Muharib Alruwaili Ayman A. M. Alameen Emad Manni Zafar Rasheed Yusuf Saleem Khan |
| author_facet | Aisha Farhana Abdullah Alsrhani Hasan Ejaz Muharib Alruwaili Ayman A. M. Alameen Emad Manni Zafar Rasheed Yusuf Saleem Khan |
| author_sort | Aisha Farhana |
| collection | DOAJ |
| description | <i>Background and Objective</i>: ATP-binding cassette (ABC) transporters are prominent drug targets due to their highly efficient trafficking capabilities and their significant physiological and clinical roles. Gaining insight into their biophysical and biomechanistic properties is crucial to maximize their pharmacological potential. <i>Materials and Methods</i>: In this study, we present the biochemical and biophysical characterization, and phylogenetic analysis of the domains of <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) ABC transporters: the exporter Rv1348 (IrtA) and the importer system Rv1349-Rv2895c (IrtB-Rv2895c), both involved in siderophore-mediated iron uptake. <i>Results</i>: Our findings reveal that the substrate-binding domain (SBD) of IrtA functions as an active monomer, while Rv2895c, which facilitates the uptake of siderophore-bound iron, exists in a dynamic equilibrium between dimeric and monomeric forms. Furthermore, ATP binding induces the dimerization of the ATPase domains in both IrtA (ATPase I) and IrtB (ATPaseII), but only the ATPase domain of IrtA (ATPase I) is active independently. We also analyzed the stability of substrate binding to the domains of the two transporters across varying temperature and pH ranges, revealing significant shifts in their activity under different conditions. Our study highlights the conformational changes that accompany substrate interaction with the transporter domains, providing insights into the fundamental mechanism required for the translocation of siderophore to the extracytoplasmic milieu by IrtB and, subsequently, import of their ferrated forms by the IrtB-Rv2895c complex. Phylogenetic analyses based on ATPase domains reveal that IrtA shares features with both archaeal and eukaryotic transporters, while IrtB is unique to mycobacterial species. <i>Conclusions</i>: Together, these findings provide valuable insights, which could accelerate the development of intervention strategies for this critical pathway pivotal in the progression of <i>M. tuberculosis</i> infection. |
| format | Article |
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| issn | 1010-660X 1648-9144 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-f4edcc69a5594bf988204786b5a815fb2025-08-20T02:04:59ZengMDPI AGMedicina1010-660X1648-91442024-11-016011189110.3390/medicina60111891Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i>Aisha Farhana0Abdullah Alsrhani1Hasan Ejaz2Muharib Alruwaili3Ayman A. M. Alameen4Emad Manni5Zafar Rasheed6Yusuf Saleem Khan7Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Aljouf, Saudi ArabiaDepartment of Pathology, College of Medicine, Qassim University, Buraidah 51452, Qassim, Saudi ArabiaDepartment of Anatomy, College of Medicine, University of Hail, Hail 55476, Hail, Saudi Arabia<i>Background and Objective</i>: ATP-binding cassette (ABC) transporters are prominent drug targets due to their highly efficient trafficking capabilities and their significant physiological and clinical roles. Gaining insight into their biophysical and biomechanistic properties is crucial to maximize their pharmacological potential. <i>Materials and Methods</i>: In this study, we present the biochemical and biophysical characterization, and phylogenetic analysis of the domains of <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) ABC transporters: the exporter Rv1348 (IrtA) and the importer system Rv1349-Rv2895c (IrtB-Rv2895c), both involved in siderophore-mediated iron uptake. <i>Results</i>: Our findings reveal that the substrate-binding domain (SBD) of IrtA functions as an active monomer, while Rv2895c, which facilitates the uptake of siderophore-bound iron, exists in a dynamic equilibrium between dimeric and monomeric forms. Furthermore, ATP binding induces the dimerization of the ATPase domains in both IrtA (ATPase I) and IrtB (ATPaseII), but only the ATPase domain of IrtA (ATPase I) is active independently. We also analyzed the stability of substrate binding to the domains of the two transporters across varying temperature and pH ranges, revealing significant shifts in their activity under different conditions. Our study highlights the conformational changes that accompany substrate interaction with the transporter domains, providing insights into the fundamental mechanism required for the translocation of siderophore to the extracytoplasmic milieu by IrtB and, subsequently, import of their ferrated forms by the IrtB-Rv2895c complex. Phylogenetic analyses based on ATPase domains reveal that IrtA shares features with both archaeal and eukaryotic transporters, while IrtB is unique to mycobacterial species. <i>Conclusions</i>: Together, these findings provide valuable insights, which could accelerate the development of intervention strategies for this critical pathway pivotal in the progression of <i>M. tuberculosis</i> infection.https://www.mdpi.com/1648-9144/60/11/1891<i>Mycobacterium tuberculosis</i>siderophore-iron uptakeABC transportersRv1348 (IrtA) and Rv2895c (IrtB)evolutionary linkage of transportersdrug targeting |
| spellingShingle | Aisha Farhana Abdullah Alsrhani Hasan Ejaz Muharib Alruwaili Ayman A. M. Alameen Emad Manni Zafar Rasheed Yusuf Saleem Khan Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> Medicina <i>Mycobacterium tuberculosis</i> siderophore-iron uptake ABC transporters Rv1348 (IrtA) and Rv2895c (IrtB) evolutionary linkage of transporters drug targeting |
| title | Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> |
| title_full | Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> |
| title_fullStr | Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> |
| title_full_unstemmed | Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> |
| title_short | Substrate-Induced Structural Dynamics and Evolutionary Linkage of Siderophore-Iron ABC Transporters of <i>Mycobacterium tuberculosis</i> |
| title_sort | substrate induced structural dynamics and evolutionary linkage of siderophore iron abc transporters of i mycobacterium tuberculosis i |
| topic | <i>Mycobacterium tuberculosis</i> siderophore-iron uptake ABC transporters Rv1348 (IrtA) and Rv2895c (IrtB) evolutionary linkage of transporters drug targeting |
| url | https://www.mdpi.com/1648-9144/60/11/1891 |
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