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Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets

Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps li...

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Autores principales: Kaur, Harbinder, Lynn, Andrew M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846249/
https://www.ncbi.nlm.nih.gov/pubmed/36685953
http://dx.doi.org/10.3389/fgene.2022.1010870
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author Kaur, Harbinder
Lynn, Andrew M.
author_facet Kaur, Harbinder
Lynn, Andrew M.
author_sort Kaur, Harbinder
collection PubMed
description Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps link the early proteins with late proteins. The FtsQBL complex is highly conserved as a component across bacteria. Pathogens like Vibrio cholerae, Mycobacterium ulcerans, Mycobacterium leprae, and Chlamydia trachomatis are the causative agents of the bacterial Neglected Tropical Diseases Cholera, Buruli ulcer, Leprosy, and Trachoma, respectively, some of which seemingly lack known homologs for some of the FtsQBL complex proteins. In the absence of experimental characterization, either due to insufficient resources or the massive increase in novel sequences generated from genomics, functional annotation is traditionally inferred by sequence similarity to a known homolog. With the advent of accurate protein structure prediction methods, features both at the fold level and at the protein interaction level can be used to identify orthologs that cannot be unambiguously identified using sequence similarity methods. Using the FtsQBL complex proteins as a case study, we report potential remote homologs using Profile Hidden Markov models and structures predicted using AlphaFold. Predicted ortholog structures show conformational similarity with corresponding E. coli proteins irrespective of their level of sequence similarity. Alphafold multimer was used to characterize remote homologs as FtsB or FtsL, when they were not sufficiently distinguishable at both the sequence or structure level, as their interactions with FtsQ and FtsW play a crucial role in their function. The structures were then analyzed to identify functionally critical regions of the proteins consistent with their homologs and delineate regions potentially useful for inhibitor discovery.
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spelling pubmed-98462492023-01-19 Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets Kaur, Harbinder Lynn, Andrew M. Front Genet Genetics Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps link the early proteins with late proteins. The FtsQBL complex is highly conserved as a component across bacteria. Pathogens like Vibrio cholerae, Mycobacterium ulcerans, Mycobacterium leprae, and Chlamydia trachomatis are the causative agents of the bacterial Neglected Tropical Diseases Cholera, Buruli ulcer, Leprosy, and Trachoma, respectively, some of which seemingly lack known homologs for some of the FtsQBL complex proteins. In the absence of experimental characterization, either due to insufficient resources or the massive increase in novel sequences generated from genomics, functional annotation is traditionally inferred by sequence similarity to a known homolog. With the advent of accurate protein structure prediction methods, features both at the fold level and at the protein interaction level can be used to identify orthologs that cannot be unambiguously identified using sequence similarity methods. Using the FtsQBL complex proteins as a case study, we report potential remote homologs using Profile Hidden Markov models and structures predicted using AlphaFold. Predicted ortholog structures show conformational similarity with corresponding E. coli proteins irrespective of their level of sequence similarity. Alphafold multimer was used to characterize remote homologs as FtsB or FtsL, when they were not sufficiently distinguishable at both the sequence or structure level, as their interactions with FtsQ and FtsW play a crucial role in their function. The structures were then analyzed to identify functionally critical regions of the proteins consistent with their homologs and delineate regions potentially useful for inhibitor discovery. Frontiers Media S.A. 2023-01-04 /pmc/articles/PMC9846249/ /pubmed/36685953 http://dx.doi.org/10.3389/fgene.2022.1010870 Text en Copyright © 2023 Kaur and Lynn. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Kaur, Harbinder
Lynn, Andrew M.
Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title_full Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title_fullStr Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title_full_unstemmed Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title_short Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets
title_sort mapping the ftsqbl divisome components in bacterial ntd pathogens as potential drug targets
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846249/
https://www.ncbi.nlm.nih.gov/pubmed/36685953
http://dx.doi.org/10.3389/fgene.2022.1010870
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