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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zervou, Maria I., Goulielmos, George N., Matalliotakis, Michail, Matalliotaki, Charoula, Spandidos, Demetrios A., Eliopoulos, Elias
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