Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains |
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Authors: | Jinlong Jian Shuai Zhao Qingyun Tian Elena Gonzalez-Gugel Jyoti Joshi Mundra Sardar MZ Uddin Ben Liu Brendon Richbourgh Ryan Brunetti Chuan-ju Liu |
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Institution: | 1. Department of Orthopaedic Surgery, New York University Medical Center, New York, NY 10003, United States;2. Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States |
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Abstract: | We previously reported that PGRN directly bound to TNF receptors (TNFR) in vitro and in chondrocytes (Tang, et al., Science, 2011). Here we report that PGRN also associated with TNFR in splenocytes, and inhibited the binding of TNFα to immune cells. Proper folding of PGRN is essential for its binding to TNFR, as DTT treatment abolished its binding to TNFR. In contrast, the binding of PGRN to Sortilin was enhanced by DTT. Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFα. Taken together, these findings provide the molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various autoimmune diseases and conditions. |
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Keywords: | PGRN progranulin TNFR tumor-necrotizing factor receptor CRD cysteine-rich domains BMDM bone marrow-derived macrophages SPR Surface plasmon resonance FTLD frontotemporal lobar degeneration Y2H yeast two-hybrid HRP horseradish peroxidase |
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