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A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3
Human HtrA3 (high-temperature requirement protease A3) is a trimeric multitasking propapoptotic serine protease associated with critical cellular functions and pathogenicity. Implicated in diseases including cancer and pre-eclampsia, its role as a tumor suppressor and potential therapeutic target ca...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993860/ https://www.ncbi.nlm.nih.gov/pubmed/31899476 http://dx.doi.org/10.1042/BCJ20190706 |
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author | Acharya, Saujanya Dutta, Shubhankar Bose, Kakoli |
author_facet | Acharya, Saujanya Dutta, Shubhankar Bose, Kakoli |
author_sort | Acharya, Saujanya |
collection | PubMed |
description | Human HtrA3 (high-temperature requirement protease A3) is a trimeric multitasking propapoptotic serine protease associated with critical cellular functions and pathogenicity. Implicated in diseases including cancer and pre-eclampsia, its role as a tumor suppressor and potential therapeutic target cannot be ignored. Therefore, elucidating its mode of activation and regulatory switch becomes indispensable towards modulating its functions with desired effects for disease intervention. Using computational, biochemical and biophysical tools, we delineated the role of all domains, their combinations and the critical phenylalanine residues in regulating HtrA3 activity, oligomerization and specificity. Our findings underline the crucial roles of the N-terminus as well as the PDZ domain in oligomerization and formation of a catalytically competent enzyme, thus providing new insights into its structure–function coordination. Our study also reports an intricate ligand-induced allosteric switch, which redefines the existing hypothesis of HtrA3 activation besides opening up avenues for modulating protease activity favorably through suitable effector molecules. |
format | Online Article Text |
id | pubmed-6993860 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69938602020-02-10 A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 Acharya, Saujanya Dutta, Shubhankar Bose, Kakoli Biochem J Cancer Human HtrA3 (high-temperature requirement protease A3) is a trimeric multitasking propapoptotic serine protease associated with critical cellular functions and pathogenicity. Implicated in diseases including cancer and pre-eclampsia, its role as a tumor suppressor and potential therapeutic target cannot be ignored. Therefore, elucidating its mode of activation and regulatory switch becomes indispensable towards modulating its functions with desired effects for disease intervention. Using computational, biochemical and biophysical tools, we delineated the role of all domains, their combinations and the critical phenylalanine residues in regulating HtrA3 activity, oligomerization and specificity. Our findings underline the crucial roles of the N-terminus as well as the PDZ domain in oligomerization and formation of a catalytically competent enzyme, thus providing new insights into its structure–function coordination. Our study also reports an intricate ligand-induced allosteric switch, which redefines the existing hypothesis of HtrA3 activation besides opening up avenues for modulating protease activity favorably through suitable effector molecules. Portland Press Ltd. 2020-01-31 2020-01-30 /pmc/articles/PMC6993860/ /pubmed/31899476 http://dx.doi.org/10.1042/BCJ20190706 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Cancer Acharya, Saujanya Dutta, Shubhankar Bose, Kakoli A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title | A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title_full | A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title_fullStr | A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title_full_unstemmed | A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title_short | A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3 |
title_sort | distinct concerted mechanism of structural dynamism defines activity of human serine protease htra3 |
topic | Cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993860/ https://www.ncbi.nlm.nih.gov/pubmed/31899476 http://dx.doi.org/10.1042/BCJ20190706 |
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