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LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation
The Mycobacterium tuberculosis kinase PknB is essential for growth and survival of the pathogen in vitro and in vivo. Here we report the results of our efforts to elucidate the mechanism of regulation of PknB activity. The specific residues in the PknB extracytoplasmic domain that are essential for...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428115/ https://www.ncbi.nlm.nih.gov/pubmed/30874556 http://dx.doi.org/10.1038/s41467-019-09223-9 |
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author | Kaur, Prabhjot Rausch, Marvin Malakar, Basanti Watson, Uchenna Damle, Nikhil P. Chawla, Yogesh Srinivasan, Sandhya Sharma, Kanika Schneider, Tanja Jhingan, Gagan Deep Saini, Deepak Mohanty, Debasisa Grein, Fabian Nandicoori, Vinay Kumar |
author_facet | Kaur, Prabhjot Rausch, Marvin Malakar, Basanti Watson, Uchenna Damle, Nikhil P. Chawla, Yogesh Srinivasan, Sandhya Sharma, Kanika Schneider, Tanja Jhingan, Gagan Deep Saini, Deepak Mohanty, Debasisa Grein, Fabian Nandicoori, Vinay Kumar |
author_sort | Kaur, Prabhjot |
collection | PubMed |
description | The Mycobacterium tuberculosis kinase PknB is essential for growth and survival of the pathogen in vitro and in vivo. Here we report the results of our efforts to elucidate the mechanism of regulation of PknB activity. The specific residues in the PknB extracytoplasmic domain that are essential for ligand interaction and survival of the bacterium are identified. The extracytoplasmic domain interacts with mDAP-containing LipidII, and this is abolished upon mutation of the ligand-interacting residues. Abrogation of ligand-binding or sequestration of the ligand leads to aberrant localization of PknB. Contrary to the prevailing hypothesis, abrogation of ligand-binding is linked to activation loop hyperphosphorylation, and indiscriminate hyperphosphorylation of PknB substrates as well as other proteins, ultimately causing loss of homeostasis and cell death. We propose that the ligand-kinase interaction directs the appropriate localization of the kinase, coupled to stringently controlled activation of PknB, and consequently the downstream processes thereof. |
format | Online Article Text |
id | pubmed-6428115 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64281152019-03-22 LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation Kaur, Prabhjot Rausch, Marvin Malakar, Basanti Watson, Uchenna Damle, Nikhil P. Chawla, Yogesh Srinivasan, Sandhya Sharma, Kanika Schneider, Tanja Jhingan, Gagan Deep Saini, Deepak Mohanty, Debasisa Grein, Fabian Nandicoori, Vinay Kumar Nat Commun Article The Mycobacterium tuberculosis kinase PknB is essential for growth and survival of the pathogen in vitro and in vivo. Here we report the results of our efforts to elucidate the mechanism of regulation of PknB activity. The specific residues in the PknB extracytoplasmic domain that are essential for ligand interaction and survival of the bacterium are identified. The extracytoplasmic domain interacts with mDAP-containing LipidII, and this is abolished upon mutation of the ligand-interacting residues. Abrogation of ligand-binding or sequestration of the ligand leads to aberrant localization of PknB. Contrary to the prevailing hypothesis, abrogation of ligand-binding is linked to activation loop hyperphosphorylation, and indiscriminate hyperphosphorylation of PknB substrates as well as other proteins, ultimately causing loss of homeostasis and cell death. We propose that the ligand-kinase interaction directs the appropriate localization of the kinase, coupled to stringently controlled activation of PknB, and consequently the downstream processes thereof. Nature Publishing Group UK 2019-03-15 /pmc/articles/PMC6428115/ /pubmed/30874556 http://dx.doi.org/10.1038/s41467-019-09223-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kaur, Prabhjot Rausch, Marvin Malakar, Basanti Watson, Uchenna Damle, Nikhil P. Chawla, Yogesh Srinivasan, Sandhya Sharma, Kanika Schneider, Tanja Jhingan, Gagan Deep Saini, Deepak Mohanty, Debasisa Grein, Fabian Nandicoori, Vinay Kumar LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title | LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title_full | LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title_fullStr | LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title_full_unstemmed | LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title_short | LipidII interaction with specific residues of Mycobacterium tuberculosis PknB extracytoplasmic domain governs its optimal activation |
title_sort | lipidii interaction with specific residues of mycobacterium tuberculosis pknb extracytoplasmic domain governs its optimal activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428115/ https://www.ncbi.nlm.nih.gov/pubmed/30874556 http://dx.doi.org/10.1038/s41467-019-09223-9 |
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