Article ; Online: Computational saturation mutagenesis to explore the effect of pathogenic mutations on extra-cellular domains of TREM2 associated with Alzheimer's and Nasu-Hakola disease.
2023 Volume 29, Issue 11, Page(s) 360
Abstract: Context: The specialised family of triggering receptors expressed on myeloid cells (TREMs) plays a pivotal role in causing neurodegenerative disorders and activating microglial anti-inflammatory responses. Nasu-Hakola disease (NHD), a rare autosomal ... ...
| Abstract | Context: The specialised family of triggering receptors expressed on myeloid cells (TREMs) plays a pivotal role in causing neurodegenerative disorders and activating microglial anti-inflammatory responses. Nasu-Hakola disease (NHD), a rare autosomal recessive disorder, has been associated with mutations in TREM2, which is also responsible for raising the risk of Alzheimer's disease (AD). Herein, we have made an endeavour to differentiate the confirmed pathogenic variants in TREM2 extra-cellular domain (ECD) linked with NHD and AD using mutation-induced fold stability change (∆∆G), with the computation of 12distinct structure-based methods through saturation mutagenesis. Correlation analysis between relative solvent accessibility (RSA) and ∆∆G expresses the discrete distributive behaviour of mutants associated with TREM2 in AD (R Methods: ConSurf algorithm and ENDscript were used to determine the position and conservation of each residue in the wild-type ECD of TREM2. The mutation-induced fold stability change (∆∆G) of confirmed pathogenic mutants associated with NHD and AD was estimated using 12 state-of-the-art structure-based protein stability tools. Furthermore, we also computed the effect of random mutation on these sites using computational saturation mutagenesis. Linear regression analysis was performed using mutants ∆∆G and RSA through GraphPad software. In addition, a comprehensive non-bonded residual interaction network (RIN) of wild type and its mutants of TREM2-ECD was enumerated using RING3.0. |
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| MeSH term(s) | Humans ; Alzheimer Disease/genetics ; Ligands ; Mutation ; Mutagenesis ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics |
| Chemical Substances | Ligands ; TREM2 protein, human ; Membrane Glycoproteins ; Receptors, Immunologic |
| Language | English |
| Publishing date | 2023-11-04 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 1284729-X |
| ISSN | 0948-5023 ; 1610-2940 |
| ISSN (online) | 0948-5023 |
| ISSN | 1610-2940 |
| DOI | 10.1007/s00894-023-05770-7 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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