We constructed a three-dimensional model of TNFRSF25 (death receptor-3; DR3), a tumor necrosis-receptor family member that is expressed on immune cells and on osteoblasts, to determine whether mutations that are linked to rheumatoid arthritis are likely to have effects on receptor function. Since the crystal structure of DR3 is not known, comparative modeling was used, aligning structural elements of the primary sequences of DR3 with TNFs which have been determined by crystallography, substituting the amino acids of the target protein for those in the known structure, introducing necessary deletions or insertions, followed by energy minimization to yield a putative structure. This approach has been validated by studies of other TNF-family receptors. The results show that the DR3 extracellular domain is comprised of four homologous cysteine-rich domains (CRDs), and that a mutation linked to rheumatoid arthritis is in a region critical for structural integrity of ligand-receptor complexes at the end of CRD3. Specifically, the D158G mutation eliminates two hydrogen bonds normally present in a N/D-T-V/D-C consensus motif typically found flanking the last cysteine of each CRD. This may cause aberrations in either T cell function or in response of bone cells to DR3 ligands, which may contribute to pathology in rheumatoid arthritis. Comparison of RA mutants to mutants in other TNFRSF receptors shows that these occur in homologous positions in CRDs, so that this site is proposed to be a 'hot spot' for mutations in TNFRSF family proteins.
"Like TNFR, DR3 also has four CRD in its extracellular domain, and although the crystal structure of DR3 has yet to be solved, the structural modeling predicts a similar structure to TNFR1 in which primary contacts with its ligand TL1A are in the 2nd and 3rd CRD , . In addition, a mutation linked to rheumatoid arthritis is in a region critical for structural integrity of ligand–receptor complexes at the end of CRD3 , . Interestingly, our data have demonstrated that the first three CRD domains of the extracellular potion of DR3, i.e. "
[Show abstract][Hide abstract] ABSTRACT: Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.
PLoS ONE 03/2014; 9(3):e92743. DOI:10.1371/journal.pone.0092743 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: En los congresos anuales de la Sociedad Española de Farmacología (SEF) hay siempre una sesión de docencia. Esta sana inquietud pedagógica de la SEF justifica que describa aquí la pauta de organización de los congresos de estudiantes de medicina, una actividad docente verdaderamente singular.
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