Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
27 02 2020
27 02 2020
Historique:
received:
05
07
2019
accepted:
13
02
2020
entrez:
29
2
2020
pubmed:
29
2
2020
medline:
11
11
2020
Statut:
epublish
Résumé
Recently, the critical roles played by genetic variants of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in Alzheimer's disease have been aggressively highlighted. However, few studies have focused on the deleterious roles of Nasu-Hakola disease (NHD) associated TREM2 variants. In order to get insights into the contributions made by these variants to neurodegeneration, we investigated the influences of four NHD associated TREM2 mutations (Y38C, W50C, T66M, and V126G) on loss-of-function, and followed this with in silico prediction and conventional molecular dynamics simulation. NHD mutations were predicted to be highly deleterious by eight different in silico bioinformatics tools and found to induce conformational changes by molecular dynamics simulation. As compared with the wild-type, the four variants produced substantial differences in the collective motions of loop regions, which not only promoted structural remodeling in the CDR2 (complementarity-determining region 2) loop but also in the CDR1 loop, by changing inter- and intra-loop hydrogen bonding networks. In addition, structural studies in a free energy landscape analysis showed that Y38, T66, and V126 are crucial for maintaining the structural features of CDR1 and CDR2 loops, and that mutations in these positions produced steric clashes and loss of ligand binding. These results showed the presence of mutations in the TREM2 ectodomain induced flexibility and caused structural alterations. Dynamical scenarios, as provided by the present study, may be critical to our understanding of the roles of these TREM2 mutations in neurodegenerative diseases.
Identifiants
pubmed: 32107424
doi: 10.1038/s41598-020-60561-x
pii: 10.1038/s41598-020-60561-x
pmc: PMC7046722
doi:
Substances chimiques
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3663Références
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