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Molecular dynamics and intracellular signalling of the TNF-R1 carrying the R92Q mutation
ECTRIMS Online Library. Malhotra S. Oct 11, 2014; 64275
Sunny Malhotra
Sunny Malhotra
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Abstract
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Background: The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene codes for TNF-R1, one of the main TNF receptors that mediates its inflammatory actions. In a recent study, serum levels of the soluble form of TNF-R1 (sTNF-R1) and cell surface mRNA expression of the full length receptor were significantly increased in patients carrying the R92Q mutation. Furthermore, R92Q carriers were younger at disease onset and progressed slower as compared to non-carriers.
Objectives: We aimed to investigate the functional changes associated with the R92Q-mutated receptor by using molecular dynamics modelling approaches and by measuring the expression of key TNF-R1 downstream intracellular mediators signalling for apoptosis and proliferation.
Methods: mRNA expression levels for TRAF2 (TNF receptor-associated factor 2) and CASP3 (caspase 3, apoptosis-related cysteine peptidase) were determined by real time PCR in peripheral blood mononuclear cells (PBMC) from 61 untreated MS patients, 9 patients carrying the R92Q mutation (CT genotype for rs4149584) and 52 R92Q non-carriers (CC genotype for rs4149584). Models of the extracellular domains of human TNF-R1 and human TNF-R1 carrying the R92Q mutation, alone or bound to TNF, were constructed using Modeller and the pdb structures 1TNF and 1TNR as templates. Structures were submitted to 50 ns of molecular dynamics (NAMD) at CESCA supercomputing facilities. The effect of R92Q mutation during protein dynamics was analysed with VMD and CMA programs.
Results: Gene expression levels for intracellular mediators of the TNF-R1 pathway were increased in R92Q carriers compared to non-carriers, and differences reached statistical significance for CASP3 (p=0.01), whereas a trend was observed for TRAF2 (p=0.07). Molecular dynamic studies revealed that the R92Q mutation increased the contact area between receptor and TNF (1070 and 1388 Å2 for native and mutated receptor) and decreased the distance between them (28.7 to 27.9 Å), whereas Van der Waals (-72 and 94 Kcal/mol) and electrostatic (-314 and -375 Kcal/mol) interaction energies increased. In vitro and in silico experiments suggest that the R92Q mutation gives rise to a stronger interaction between the receptor and ligand, which results in the potentiation of the TNF-R1 signalling pathway.
Conclusions: These functional changes associated with the mutated TNF-R1 receptor may be related with the modulation in disease course reported in MS patients carrying the R92Q mutation.
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