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Molecular dynamics and intracellular signaling of the TNF-R1 with the R92Q mutation.

Abstract

The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene encodes the TNF-R1, one of the main TNF receptors that mediates its inflammatory actions. In a recent study, serum levels of the soluble TNF-R1 and mRNA levels of the full-length receptor were found to be significantly increased in multiple sclerosis (MS) patients carrying the R92Q mutation. Interestingly, R92Q-mutated patients were younger at disease onset and progressed slower as compared to non-carriers. Building on these previous findings, here we aimed to investigate by means of both in silico and in vitro approaches the mechanisms relating the R92Q substitution with functional changes of the receptor and their potential effects modulating MS disease course. Models of the extracellular domains of the human TNF-R1 and human TNF-R1 carrying the R92Q mutation, alone or bound to TNF, were constructed and submitted to molecular dynamics. TRAF2 and CASP3 mRNA expression levels were determined by real-time PCR in peripheral blood mononuclear cells (PBMC) from 61 MS patients, 9 R92Q carriers and 52 non-carriers (CT and CC genotypes for SNP rs4149584, respectively). Molecular dynamic studies revealed that the R92Q mutation increased the contact area between receptor and TNF (1070 and 1388Å(2) for native and mutated receptor) and decreased the distance between them (28.7 to 27.9Å), while Van der Waals and electrostatic interaction energies were increased. In PBMC from MS patients carrying the R92Q mutation, CASP3 mRNA expression levels were significantly increased compared to non-carriers, whereas a trend was observed for TRAF2. These data suggest that the R92Q mutation gives rise to a stronger interaction between the receptor and its ligand, which results in the potentiation of TNF-mediated pathways. Although further studies are needed, these functional changes may be related with the modulation in disease course reported in MS patients carrying the R92Q mutation.

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  • Authors+Show Affiliations

    ,

    Computational Biochemistry and Biophysics Laboratory (CBBL), U_Science Tech (UST), Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), 08500 Vic, Barcelona, Spain.

    ,

    Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.

    ,

    Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.

    ,

    Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.

    Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.

    Source

    Journal of neuroimmunology 289: 2015 Dec 15 pg 12-20

    MeSH

    Arginine
    Biological Evolution
    Caspase 3
    Glutamine
    Humans
    Models, Molecular
    Mutation
    Nonlinear Dynamics
    RNA, Messenger
    Receptors, Tumor Necrosis Factor, Type I
    Signal Transduction
    TNF Receptor-Associated Factor 2

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26616867

    Citation

    Agulló, Luis, et al. "Molecular Dynamics and Intracellular Signaling of the TNF-R1 With the R92Q Mutation." Journal of Neuroimmunology, vol. 289, 2015, pp. 12-20.
    Agulló L, Malhotra S, Fissolo N, et al. Molecular dynamics and intracellular signaling of the TNF-R1 with the R92Q mutation. J Neuroimmunol. 2015;289:12-20.
    Agulló, L., Malhotra, S., Fissolo, N., Montalban, X., & Comabella, M. (2015). Molecular dynamics and intracellular signaling of the TNF-R1 with the R92Q mutation. Journal of Neuroimmunology, 289, pp. 12-20. doi:10.1016/j.jneuroim.2015.10.003.
    Agulló L, et al. Molecular Dynamics and Intracellular Signaling of the TNF-R1 With the R92Q Mutation. J Neuroimmunol. 2015 Dec 15;289:12-20. PubMed PMID: 26616867.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Molecular dynamics and intracellular signaling of the TNF-R1 with the R92Q mutation. AU - Agulló,Luis, AU - Malhotra,Sunny, AU - Fissolo,Nicolás, AU - Montalban,Xavier, AU - Comabella,Manuel, Y1 - 2015/10/22/ PY - 2015/06/11/received PY - 2015/09/18/revised PY - 2015/10/08/accepted PY - 2015/12/1/entrez PY - 2015/12/1/pubmed PY - 2016/3/15/medline KW - CASP3 KW - Molecular dynamics KW - Multiple sclerosis KW - R92Q mutation KW - TNF receptor 1 KW - TNF receptor-associated periodic syndrome KW - TRAF2 KW - Tumor necrosis factor KW - mRNA expression SP - 12 EP - 20 JF - Journal of neuroimmunology JO - J. Neuroimmunol. VL - 289 N2 - The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene encodes the TNF-R1, one of the main TNF receptors that mediates its inflammatory actions. In a recent study, serum levels of the soluble TNF-R1 and mRNA levels of the full-length receptor were found to be significantly increased in multiple sclerosis (MS) patients carrying the R92Q mutation. Interestingly, R92Q-mutated patients were younger at disease onset and progressed slower as compared to non-carriers. Building on these previous findings, here we aimed to investigate by means of both in silico and in vitro approaches the mechanisms relating the R92Q substitution with functional changes of the receptor and their potential effects modulating MS disease course. Models of the extracellular domains of the human TNF-R1 and human TNF-R1 carrying the R92Q mutation, alone or bound to TNF, were constructed and submitted to molecular dynamics. TRAF2 and CASP3 mRNA expression levels were determined by real-time PCR in peripheral blood mononuclear cells (PBMC) from 61 MS patients, 9 R92Q carriers and 52 non-carriers (CT and CC genotypes for SNP rs4149584, respectively). Molecular dynamic studies revealed that the R92Q mutation increased the contact area between receptor and TNF (1070 and 1388Å(2) for native and mutated receptor) and decreased the distance between them (28.7 to 27.9Å), while Van der Waals and electrostatic interaction energies were increased. In PBMC from MS patients carrying the R92Q mutation, CASP3 mRNA expression levels were significantly increased compared to non-carriers, whereas a trend was observed for TRAF2. These data suggest that the R92Q mutation gives rise to a stronger interaction between the receptor and its ligand, which results in the potentiation of TNF-mediated pathways. Although further studies are needed, these functional changes may be related with the modulation in disease course reported in MS patients carrying the R92Q mutation. SN - 1872-8421 UR - https://www.unboundmedicine.com/medline/citation/26616867/Molecular_dynamics_and_intracellular_signaling_of_the_TNF_R1_with_the_R92Q_mutation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-5728(15)30049-7 DB - PRIME DP - Unbound Medicine ER -