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Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function

Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extrace...

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Autores principales: Dash, Raju, Munni, Yeasmin Akter, Mitra, Sarmistha, Choi, Ho Jin, Jahan, Sultana Israt, Chowdhury, Apusi, Jang, Tae Jung, Moon, Il Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174165/
https://www.ncbi.nlm.nih.gov/pubmed/35672339
http://dx.doi.org/10.1038/s41598-022-13120-5
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author Dash, Raju
Munni, Yeasmin Akter
Mitra, Sarmistha
Choi, Ho Jin
Jahan, Sultana Israt
Chowdhury, Apusi
Jang, Tae Jung
Moon, Il Soo
author_facet Dash, Raju
Munni, Yeasmin Akter
Mitra, Sarmistha
Choi, Ho Jin
Jahan, Sultana Israt
Chowdhury, Apusi
Jang, Tae Jung
Moon, Il Soo
author_sort Dash, Raju
collection PubMed
description Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extracellular domain of TREM2. However, the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in TREM2 on disease progression remain unknown. In this study, we identified several high-risk nsSNPs in the TREM2 gene using various deleterious SNP predicting algorithms and analyzed their destabilizing effects on the ligand recognizing region of the TREM2 immunoglobulin (Ig) domain by molecular dynamics (MD) simulation. Cumulative prediction by all tools employed suggested the three most deleterious nsSNPs involved in loss of TREM2 function are rs549402254 (W50S), rs749358844 (R52C), and rs1409131974 (D104G). MD simulation showed that these three variants cause substantial structural alterations and conformational remodeling of the apical loops of the TREM2 Ig domain, which is responsible for ligand recognition. Detailed analysis revealed that these variants substantially increased distances between apical loops and induced conformation remodeling by changing inter-loop nonbonded contacts. Moreover, all nsSNPs changed the electrostatic potentials near the putative ligand-interacting region (PLIR), which suggested they might reduce specificity or loss of binding affinity for TREM2 ligands. Overall, this study identifies three potential high-risk nsSNPs in the TREM2 gene. We propose further studies on the molecular mechanisms responsible for loss of TREM2 function and the associations between TREM2 nsSNPs and neurodegenerative diseases.
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spelling pubmed-91741652022-06-09 Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function Dash, Raju Munni, Yeasmin Akter Mitra, Sarmistha Choi, Ho Jin Jahan, Sultana Israt Chowdhury, Apusi Jang, Tae Jung Moon, Il Soo Sci Rep Article Single nucleotide variations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with many neurodegenerative diseases, including Nasu-Hakola disease (NHD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease because they disrupt ligand binding to the extracellular domain of TREM2. However, the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in TREM2 on disease progression remain unknown. In this study, we identified several high-risk nsSNPs in the TREM2 gene using various deleterious SNP predicting algorithms and analyzed their destabilizing effects on the ligand recognizing region of the TREM2 immunoglobulin (Ig) domain by molecular dynamics (MD) simulation. Cumulative prediction by all tools employed suggested the three most deleterious nsSNPs involved in loss of TREM2 function are rs549402254 (W50S), rs749358844 (R52C), and rs1409131974 (D104G). MD simulation showed that these three variants cause substantial structural alterations and conformational remodeling of the apical loops of the TREM2 Ig domain, which is responsible for ligand recognition. Detailed analysis revealed that these variants substantially increased distances between apical loops and induced conformation remodeling by changing inter-loop nonbonded contacts. Moreover, all nsSNPs changed the electrostatic potentials near the putative ligand-interacting region (PLIR), which suggested they might reduce specificity or loss of binding affinity for TREM2 ligands. Overall, this study identifies three potential high-risk nsSNPs in the TREM2 gene. We propose further studies on the molecular mechanisms responsible for loss of TREM2 function and the associations between TREM2 nsSNPs and neurodegenerative diseases. Nature Publishing Group UK 2022-06-07 /pmc/articles/PMC9174165/ /pubmed/35672339 http://dx.doi.org/10.1038/s41598-022-13120-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 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 Article
Dash, Raju
Munni, Yeasmin Akter
Mitra, Sarmistha
Choi, Ho Jin
Jahan, Sultana Israt
Chowdhury, Apusi
Jang, Tae Jung
Moon, Il Soo
Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title_full Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title_fullStr Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title_full_unstemmed Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title_short Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function
title_sort dynamic insights into the effects of nonsynonymous polymorphisms (nssnps) on loss of trem2 function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174165/
https://www.ncbi.nlm.nih.gov/pubmed/35672339
http://dx.doi.org/10.1038/s41598-022-13120-5
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