کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10815726 | 1058500 | 2010 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Dual function of cysteine rich domain (CRD) 1 of TNF receptor type 1: Conformational stabilization of CRD2 and control of receptor responsiveness
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کلمات کلیدی
sTNFzVADfmkDeath Inducing Signalling ComplexFAS-associating protein with death domainTNFSignalling complexmTNFpLADSoluble TNFTNFRFADDDISCCRDmAbamino acid - آمینو اسیدMonoclonal antibody - آنتی بادی مونوکلونالcysteine rich domain - دامنه غنی از سیستینRoom temperature - دمای اتاقMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیtumor necrosis factor - فاکتور نکروز تومورMouse fibroblast - فیبروبلاست موسwild type - نوع وحشیGlycoprotein D - گلیکوپروتئین DTNF receptor - گیرنده TNF
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The proinflammatory cytokine Tumor Necrosis Factor (TNF) exists as a homotrimer, capable of binding three receptor molecules. However, signal competent ligand/receptor complexes form large clusters, likely to be stabilized by additional molecular interactions. Both TNF receptors, TNFR1 and TNFR2, contain four cysteine rich domains (CRD) in their extracellular parts. Previous work showed that the membrane distal CRD1 carries a homophilic interaction domain. Here, we investigated the functional role of CRD1 and its two submodules, A1CRD1 and B2CRD1, in a TNFR1-Fas chimera model system. Removal of CRD1 abolishes TNF binding. In line with these data, molecular dynamics simulations suggest that B2CRD1 of TNFR1 serves as a scaffold to stabilize CRD2 in a conformation necessary for high affinity ligand binding. Deletion of only the N-terminal half of CRD1 (ÎA1CRD1) of TNFR1 marginally affects ligand binding but abrogates responsiveness towards soluble TNF and reduces effectiveness as a dominant negative inhibitor of wild type TNFR1. A TNFR1-derived molecule containing the CRD1 from TNFR2 also shows reduced responsiveness to soluble TNF. These data strongly suggest that CRD1 is not only crucially involved in multimerization of unligated receptors, but is also directly involved in formation of signal competent ligand/receptor clusters, thereby controlling receptor responsiveness.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 22, Issue 3, March 2010, Pages 404-414
Journal: Cellular Signalling - Volume 22, Issue 3, March 2010, Pages 404-414
نویسندگان
Marcus Branschädel, Andrew Aird, Andrea Zappe, Carsten Tietz, Anja Krippner-Heidenreich, Peter Scheurich,