A tetravalent peptide that binds to the RANK-binding region of TRAF6 via a multivalent interaction efficiently inhibits osteoclast differentiation
A tetravalent peptide that binds to the RANK-binding region of TRAF6 via a multivalent interaction efficiently inhibits osteoclast differentiation
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DOI：
10.1016/j.bbrc.2022.10.075
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发表时间：
2022-11-02
影响因子：
3.1
通讯作者：
Nishikawa, Kiyotaka
中科院分区：
文献类型：
--
作者：
Anzai, Masataka;Takahashi, Miho Watanabe;Nishikawa, Kiyotaka
抑制破骨细胞分化是治疗骨质疏松症和类风湿性关节炎的一种有前途的方法。核因子κ B受体激活因子（NF-kB）（RANK）是破骨细胞分化的必需分子，其与肿瘤坏死因子（TNF）受体相关因子6（TRAF 6）相互作用以抑制下游信号。RANK和TRAF 6均具有同源三聚体结构，在RANK的Pro-X-Glu-X-X-（芳香/酸性）基序和TRAF 6的C-末端结构域（TRAF-C）之间形成多价相互作用，显著增加结合亲和力。在这里，我们设计了一个四价肽，RANK-tet，含有TRAF-C结合基序的RANK，并发现RANK-tet结合TRAF-C具有高亲和力。相比之下，具有相同TRAF-C结合基序的单体形式的RANK-tet（RANK-mono）不与TRAF-C结合，这清楚地表明，与TRAF-C的高亲和力结合严格需要多价相互作用。RANK-tet不与一系列RANK结合区氨基酸取代的TRAF-C突变体结合，表明RANK-tet特异性靶向TRAF-C的RANK结合区。在TRAF-C结合基序的每个C-末端具有聚精氨酸残基的RANK-tet的细胞渗透形式有效抑制RANK配体（RANKL）诱导的骨髓细胞向破骨细胞的分化。因此，该化合物可以是有效的抗破骨细胞生成剂。(c)爱思唯尔公司All rights reserved.
Inhibition of osteoclast differentiation is a promising approach for the treatment of osteoporosis and rheumatoid arthritis. Receptor activator of nuclear factor kappa B (NF-kB) (RANK), which is an essential molecule for osteoclast differentiation, interacts with tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) to transduce downstream signals. Both RANK and TRAF6 have homo-trimeric struc-tures, forming a multivalent interaction between the Pro-X-Glu-X-X-(aromatic/acidic) motif of RANK and the C-terminal domain of TRAF6 (TRAF-C), that markedly increases the binding affinity. Here, we designed a tetravalent peptide, RANK-tet, containing the TRAF-C-binding motif of RANK and found that RANK-tet binds to TRAF-C with high affinity. In contrast, a monomeric form of RANK-tet (RANK-mono) with the same TRAF-C-binding motif did not bind to TRAF-C, clearly indicating the multivalent inter-action is strictly required for the high-affinity binding to TRAF-C. RANK-tet did not bind to a series of TRAF-C-mutants with an amino acid substitution in the RANK-binding region, indicating that RANK-tet specifically targets the RANK-binding region of TRAF-C. A cell-permeable form of RANK-tet that has poly-Arg residues at each C-terminal of the TRAF-C-binding motif efficiently inhibited the RANK ligand (RANKL)-induced differentiation of bone marrow cells to osteoclasts. Thus, this compound can be an effective anti-osteoclastogenic agent. (c) 2022 Elsevier Inc. All rights reserved.