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Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex
BACKGROUND: The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861233/ https://www.ncbi.nlm.nih.gov/pubmed/35190906 http://dx.doi.org/10.1186/s43141-022-00300-z |
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author | Fayez, Alaaeldin G. Eldeen, Ghada Nour Zarouk, Waheba A. Hamed, Khaled Ramadan, Abeer Foda, Bardees M. Kobesiy, Maha M. Zekrie, Mai E. Lotfy, Randa S. Sokkar, Mona F. El-Bassyouni, Hala T. |
author_facet | Fayez, Alaaeldin G. Eldeen, Ghada Nour Zarouk, Waheba A. Hamed, Khaled Ramadan, Abeer Foda, Bardees M. Kobesiy, Maha M. Zekrie, Mai E. Lotfy, Randa S. Sokkar, Mona F. El-Bassyouni, Hala T. |
author_sort | Fayez, Alaaeldin G. |
collection | PubMed |
description | BACKGROUND: The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. RESULTS: It was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (K(d)), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. CONCLUSION: The molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients. |
format | Online Article Text |
id | pubmed-8861233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-88612332022-03-08 Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex Fayez, Alaaeldin G. Eldeen, Ghada Nour Zarouk, Waheba A. Hamed, Khaled Ramadan, Abeer Foda, Bardees M. Kobesiy, Maha M. Zekrie, Mai E. Lotfy, Randa S. Sokkar, Mona F. El-Bassyouni, Hala T. J Genet Eng Biotechnol Research BACKGROUND: The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. RESULTS: It was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (K(d)), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. CONCLUSION: The molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients. Springer Berlin Heidelberg 2022-02-21 /pmc/articles/PMC8861233/ /pubmed/35190906 http://dx.doi.org/10.1186/s43141-022-00300-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Fayez, Alaaeldin G. Eldeen, Ghada Nour Zarouk, Waheba A. Hamed, Khaled Ramadan, Abeer Foda, Bardees M. Kobesiy, Maha M. Zekrie, Mai E. Lotfy, Randa S. Sokkar, Mona F. El-Bassyouni, Hala T. Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title | Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title_full | Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title_fullStr | Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title_full_unstemmed | Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title_short | Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex |
title_sort | dynamic disequilibrium-based pathogenicity model in mutated pyrin’s b30.2 domain—casp1/p20 complex |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861233/ https://www.ncbi.nlm.nih.gov/pubmed/35190906 http://dx.doi.org/10.1186/s43141-022-00300-z |
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