{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Anzai M"],"funding":["MEXT | Japan Society for the Promotion of Science","MEXT | Japan Science and Technology Agency (JST)","MEXT | Japan Society for the Promotion of Science (JSPS)","University of Tokyo","MEXT | Japan Science and Technology Agency"],"pagination":["643"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12015293"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(1)"],"pubmed_abstract":["Bone-destructive diseases are caused by dysregulated osteoclastogenesis. Osteoclast differentiation is positively regulated by the ligand for receptor activator of nuclear factor kappa B (RANKL) binding to the RANK on progenitor cells. RANK then forms a multivalent interaction with an adapter molecule, tumor necrosis factor receptor-associated factor 6 (TRAF6), to transduce various downstream signals. We used affinity-based screening of a multivalent random-peptide library to identify a tetravalent peptide, WHD-tet, that binds to the RANK-binding region of TRAF6 through a multivalent interaction. CR4-WHD-tet, a cell-permeable form of WHD-tet, efficiently inhibited the RANKL-induced differentiation of bone-marrow cells to osteoclasts and osteoclastogenesis in a mouse model. CR4-WHD-tet specifically inhibited the recruitment of MAPK kinase 3 to TRAF6 without affecting other signal transducers in a late stage of differentiation, inhibiting the activation of p38-MAPK, which promotes the final stage. Thus, the interaction modulator CR4-WHD-tet fine-tunes the formation of a critical signaling complex to inhibit osteoclastogenesis."],"journal":["Communications biology"],"pubmed_title":["Clustered peptide regulating the multivalent interaction between RANK and TRAF6 inhibits osteoclastogenesis by fine-tuning signals."],"pmcid":["PMC12015293"],"funding_grant_id":["JPMJSP2129","JP22J11001"],"pubmed_authors":["Kawabata H","Waku T","Ikegami A","Inoue JI","Anzai M","Watanabe-Takahashi M","Okuda Y","Sakurai H","Nishikawa K","Masuda Y"],"additional_accession":[]},"is_claimable":false,"name":"Clustered peptide regulating the multivalent interaction between RANK and TRAF6 inhibits osteoclastogenesis by fine-tuning signals.","description":"Bone-destructive diseases are caused by dysregulated osteoclastogenesis. Osteoclast differentiation is positively regulated by the ligand for receptor activator of nuclear factor kappa B (RANKL) binding to the RANK on progenitor cells. RANK then forms a multivalent interaction with an adapter molecule, tumor necrosis factor receptor-associated factor 6 (TRAF6), to transduce various downstream signals. We used affinity-based screening of a multivalent random-peptide library to identify a tetravalent peptide, WHD-tet, that binds to the RANK-binding region of TRAF6 through a multivalent interaction. CR4-WHD-tet, a cell-permeable form of WHD-tet, efficiently inhibited the RANKL-induced differentiation of bone-marrow cells to osteoclasts and osteoclastogenesis in a mouse model. CR4-WHD-tet specifically inhibited the recruitment of MAPK kinase 3 to TRAF6 without affecting other signal transducers in a late stage of differentiation, inhibiting the activation of p38-MAPK, which promotes the final stage. Thus, the interaction modulator CR4-WHD-tet fine-tunes the formation of a critical signaling complex to inhibit osteoclastogenesis.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Apr","modification":"2025-07-01T03:05:14.16Z","creation":"2025-07-01T03:05:14.16Z"},"accession":"S-EPMC12015293","cross_references":{"pubmed":["40263556"],"doi":["10.1038/s42003-025-08047-2"]}}