Inhibition of RANKL-mediated osteoclast differentiation by selective TRAF6 decoy peptides |
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Authors: | Poblenz Ann T Jacoby Joerg J Singh Sujay Darnay Bryant G |
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Institution: | Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Box 143, 1515 Holcombe Blvd., Houston, TX 77030, USA. |
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Abstract: | RANK and RANKL are essential mediators of osteoclastogenesis. RANK interacts with members of the tumor necrosis factor receptor-associated factor (TRAF) family, of which TRAF6 is the critical signaling molecule. We identified a unique TRAF6-binding motif in RANK, which was subsequently co-crystallized with TRAF6 revealing distinct molecular interactions. A cell-permeable TRAF6 decoy peptide (T6DP) was shown to specifically target TRAF6 and inhibit RANKL-mediated signaling. In this study, we identified a core motif for binding to TRAF6 by generating a series of deletion mutants linked via palmitate as a means to internalize the peptide, thus making a smaller scaffold for intracellular delivery. The core motif of RKIPTEDEY inhibited RANKL-mediated osteoclastogenesis and bone resorption. In contrast, TRAF2/5 decoy peptides appeared to have no affect. Thus, disruption of the RANK-TRAF6 interaction may prove useful as a novel target for the development of a small molecule therapeutic agent for the treatment of bone-related diseases. |
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Keywords: | TNF tumor necrosis factor GST glutathione S-transferase TRAF TNF receptor-associated factor RANK receptor activator of NF-κB HEK human embryonic kidney NF-κB nuclear factor-κB RANKL RANK ligand TRAP tartrate-resistant acid phosphatase SDS sodium dodecylsulfate |
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