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In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain

PURPOSE: The objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that cau...

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Autores principales: Padarti, Akhil, Belkin, Ofek, Abou-Fadel, Johnathan, Zhang, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808078/
https://www.ncbi.nlm.nih.gov/pubmed/35128084
http://dx.doi.org/10.1016/j.bbrep.2022.101218
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author Padarti, Akhil
Belkin, Ofek
Abou-Fadel, Johnathan
Zhang, Jun
author_facet Padarti, Akhil
Belkin, Ofek
Abou-Fadel, Johnathan
Zhang, Jun
author_sort Padarti, Akhil
collection PubMed
description PURPOSE: The objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs). METHODS: The nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database searches, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of mutations on the tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of nsSNPs on the tertiary structure of PTB Cores. RESULTS: Our mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, predicted that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 PTB function. CONCLUSION: Utilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results predicted that the pathogenic amino acid substitutions lead to only subtle changes locally, confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of independently functional dual cores in the CCM2 typical PTB domain.
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spelling pubmed-88080782022-02-04 In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain Padarti, Akhil Belkin, Ofek Abou-Fadel, Johnathan Zhang, Jun Biochem Biophys Rep Short Communication PURPOSE: The objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs). METHODS: The nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database searches, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of mutations on the tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of nsSNPs on the tertiary structure of PTB Cores. RESULTS: Our mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, predicted that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 PTB function. CONCLUSION: Utilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results predicted that the pathogenic amino acid substitutions lead to only subtle changes locally, confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of independently functional dual cores in the CCM2 typical PTB domain. Elsevier 2022-01-27 /pmc/articles/PMC8808078/ /pubmed/35128084 http://dx.doi.org/10.1016/j.bbrep.2022.101218 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Short Communication
Padarti, Akhil
Belkin, Ofek
Abou-Fadel, Johnathan
Zhang, Jun
In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title_full In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title_fullStr In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title_full_unstemmed In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title_short In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain
title_sort in-silico analysis of nonsynonymous genomic variants within ccm2 gene reaffirm the existence of dual cores within typical ptb domain
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808078/
https://www.ncbi.nlm.nih.gov/pubmed/35128084
http://dx.doi.org/10.1016/j.bbrep.2022.101218
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