Manipulation of receptor oligomerization as a strategy to inhibit signaling by TNF superfamily members.
Manipulation of receptor oligomerization as a strategy to inhibit signaling by TNF superfamily members.
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DOI：
10.1126/scisignal.2004948
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发表时间：
2014-08-19
影响因子：
7.3
通讯作者：
Teitelbaum SL
中科院分区：
文献类型：
--
作者：
Warren JT;Nelson CA;Decker CE;Zou W;Fremont DH;Teitelbaum SL
核因子-κB受体激活剂（RANK）响应其配体RANKL（细胞因子肿瘤坏死因子（TNF）超家族成员）的信号传导刺激破骨细胞形成和骨吸收。因此，这种配体-受体对是各种疾病如骨质疏松症和骨转移的治疗靶点。RANKL作为生理同源三聚体存在，每个单体识别RANK或抗破骨细胞生成诱饵受体骨保护素（OPG）的单个分子。我们设计了一种RANKL蛋白，其中RANKL的所有三个单体都编码为一条多肽链，这使我们能够独立控制每个结合界面的受体结合。为了产生有效的RANK抑制剂，我们使用无偏正向遗传方法来鉴定RANKL中的突变，这些突变对RANK的亲和力增加了500倍，但对RANKL的天然诱饵受体骨保护素的亲和力降低。将受体阻断突变引入这种高亲和力RANKL变体中，产生了一种突变RANKL，该突变RANKL在体外完全抑制野生型RANKL诱导的破骨细胞生成和小鼠骨吸收。我们的方法可以推广到能够抑制其他TNF受体信号传导系统，这涉及广泛的病理条件。
Signaling by receptor activator of nuclear factor-κB (RANK) in response to its ligand RANKL, which is a member of the tumor necrosis factor (TNF) superfamily of cytokines, stimulates osteoclast formation and bone resorption. Thus, this ligand-receptor pair is a therapeutic target for various disorders, such as osteoporosis and skeletal metastasis. RANKL exists as a physiological homotrimer with each monomer recognizing a single molecule of RANK or the anti-osteoclastogenic decoy receptor osteoprotegerin (OPG). We engineered a RANKL protein in which all three monomers of RANKL were encoded as a single polypeptide chain, which enabled us to independently control receptor-binding at each binding interface. To generate an effective RANK inhibitor, we used an unbiased forward genetic approach to identify mutations in RANKL that had a 500-fold increased affinity for RANK, but had decreased affinity for the natural decoy receptor for RANKL, osteoprotegerin. Incorporating receptor-blocking mutations into this high-affinity RANKL variant generated a mutant RANKL that completely inhibited wild-type RANKL–induced osteoclastogenesis in vitro and bone resorption in mice. Our approach may be generalized to enable the inhibition of other TNF receptor signaling systems, which are implicated in wide range of pathological conditions.
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影响因子：
4
作者：
DeSelm, Carl J.;Takahata, Yoshifumi;Warren, Julia;Chappel, Jean C.;Khan, Taimur;Li, Xiaoxia;Liu, Caini;Choi, Yongwon;Kim, Youngmi Faith;Zou, Wei;Teitelbaum, Steven L.
通讯作者：
Teitelbaum, Steven L.
影响因子：
9
作者：
通讯作者：
--
影响因子：
6.8
作者：
Gai, S. Annie;Wittrup, K. Dane
通讯作者：
Wittrup, K. Dane
RANKL-RANK 相互作用和信号传导的结构和功能见解
影响因子：
4.4
作者：
Liu, Changzhen;Walter, Thomas S.;Gao, Bin
通讯作者：
Gao, Bin
影响因子：
15.9
作者：
Lam, J;Nelson, CA;Fremont, DH
通讯作者：
Fremont, DH