Cargando…
Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach
Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947897/ https://www.ncbi.nlm.nih.gov/pubmed/31974608 http://dx.doi.org/10.3892/mmr.2019.10862 |
_version_ | 1783485650337529856 |
---|---|
author | Zervou, Maria I. Goulielmos, George N. Matalliotakis, Michail Matalliotaki, Charoula Spandidos, Demetrios A. Eliopoulos, Elias |
author_facet | Zervou, Maria I. Goulielmos, George N. Matalliotakis, Michail Matalliotaki, Charoula Spandidos, Demetrios A. Eliopoulos, Elias |
author_sort | Zervou, Maria I. |
collection | PubMed |
description | Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel and already known variants in ADA2, this study aimed to further investigate the functional significance of the rare variants detected, namely p.Gly47Arg, p.Gly47Ala, p.Arg8Trp, p.Leu351Gln and p.Ala357Thr, by using a structural biological approach. Three-dimensional models of the mutants were developed and their three-dimensional (3D) structures were subjected to detailed interaction and conformational analyses. This led to suggestions that the novel mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme. It was thus concluded that the Arg8Trp and Gly47Arg mutations affect the position and interaction of the dimer-associated HN1 helical structure and therefore, dimer formation and stabilization, while Leu351Gln and Ala357Thr influence the metal coordination in the active site. These findings shed further light onto the structural consequences of the mutations under investigation. |
format | Online Article Text |
id | pubmed-6947897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-69478972020-01-13 Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach Zervou, Maria I. Goulielmos, George N. Matalliotakis, Michail Matalliotaki, Charoula Spandidos, Demetrios A. Eliopoulos, Elias Mol Med Rep Articles Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel and already known variants in ADA2, this study aimed to further investigate the functional significance of the rare variants detected, namely p.Gly47Arg, p.Gly47Ala, p.Arg8Trp, p.Leu351Gln and p.Ala357Thr, by using a structural biological approach. Three-dimensional models of the mutants were developed and their three-dimensional (3D) structures were subjected to detailed interaction and conformational analyses. This led to suggestions that the novel mutations found may affect the formation/stability of the homodimer or may influence the activity of the enzyme. It was thus concluded that the Arg8Trp and Gly47Arg mutations affect the position and interaction of the dimer-associated HN1 helical structure and therefore, dimer formation and stabilization, while Leu351Gln and Ala357Thr influence the metal coordination in the active site. These findings shed further light onto the structural consequences of the mutations under investigation. D.A. Spandidos 2020-02 2019-12-05 /pmc/articles/PMC6947897/ /pubmed/31974608 http://dx.doi.org/10.3892/mmr.2019.10862 Text en Copyright: © Zervou et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Zervou, Maria I. Goulielmos, George N. Matalliotakis, Michail Matalliotaki, Charoula Spandidos, Demetrios A. Eliopoulos, Elias Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title | Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title_full | Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title_fullStr | Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title_full_unstemmed | Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title_short | Role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: A structural biological approach |
title_sort | role of adenosine deaminase 2 gene variants in pediatric deficiency of adenosine deaminase 2: a structural biological approach |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947897/ https://www.ncbi.nlm.nih.gov/pubmed/31974608 http://dx.doi.org/10.3892/mmr.2019.10862 |
work_keys_str_mv | AT zervoumariai roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach AT goulielmosgeorgen roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach AT matalliotakismichail roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach AT matalliotakicharoula roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach AT spandidosdemetriosa roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach AT eliopouloselias roleofadenosinedeaminase2genevariantsinpediatricdeficiencyofadenosinedeaminase2astructuralbiologicalapproach |