Structural and Functional Insights of RANKL-RANK Interaction and Signaling
Structural and Functional Insights of RANKL-RANK Interaction and Signaling
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RANKL-RANK 相互作用和信号传导的结构和功能见解
DOI：
10.4049/jimmunol.0904033
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发表时间：
2010-06-15
影响因子：
4.4
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Liu, Changzhen;Walter, Thomas S.;Gao, Bin
骨重塑涉及破骨细胞的骨吸收和成骨细胞的骨合成，并受到nf - κ B配体受体激活剂(RANKL)/ nf - κ B受体激活剂(RANK)/骨保护素分子三联体的严格调控。RANKL是TNF超家族的一员，通过与其受体RANK相互作用诱导破骨细胞分化、活化和存活。诱饵受体骨保护素通过与RANKL结合抑制破骨细胞的形成。这种分子三位一体的失衡会导致疾病，包括骨质疏松症和类风湿性关节炎。在这项研究中，我们报道了未配位的RANK及其与RANKL复合物的晶体结构，并阐明了受体对功能的关键残基。RANK代表最长的TNFR，具有四个完整的富含半胱氨酸结构域（CRDs），其中CRD4通过钠离子和与CRD3的刚性连接来稳定。在关联上，RANK通过CRD2和CRD3之间的铰链区域移动，与RANKL密切接触；在TNFR超家族1A与其配体的结合中出现了以前未见的重大结构变化。RANK和RANKL之间的高亲和力相互作用，通过两者之间的持续接触而不是通常观察到的补丁相互作用来维持，是功能所必需的，因为突变引起的亲和力轻微降低会显著破坏破骨细胞的形成。RANK和RANKL-RANK复合物的结构以及本文中提出的生物学数据不仅对我们理解信号机制的具体性质和患者中发现的疾病相关突变，而且对基于结构的药物设计至关重要。中华免疫学杂志，2010,18(4):691 -691。
Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-kappa B ligand (RANKL)/receptor activator of the NF-kappa B (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL-RANK complex and the biological data presented in the paper are essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design. The Journal of Immunology, 2010, 184: 6910-6919.