Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity
Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity
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DOI：
10.1038/emboj.2009.37
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发表时间：
2009-04-08
期刊：
影响因子：
11.4
通讯作者：
Mueller, Thomas D.
中科院分区：
文献类型：
--
作者：
Kotzsch, Alexander;Nickel, Joachim;Mueller, Thomas D.
生长和分化因子5 （GDF-5）信号传导失调是tgf - β超家族的一员，与骨骼畸形密切相关。gdf -5介导的信号转导涉及BMP -I型受体、BMP - ia和BMP - ib。然而，GDF-5或BMPR-IB的突变导致相似的表型，这表明在软骨形成中，GDF-5信号通路似乎完全通过BMPR-IB介导。在这里，我们提出了对GDF-5: BMPR-IB复合物的结构见解，揭示了bbmpr - ib的结合特异性是如何在分子水平上产生的。在BMPR-IB中，配体结合表位内的环的功能类似于锁存器，允许GDF-5的高亲和力结合。在BMPR-IA中，这个锁存器呈闭合构象，导致空间排斥。新的结构数据现在也提供了GDF-5表型相关错义突变如何损害受体结合和激活的分子基础。
Dysregulation of growth and differentiation factor 5 (GDF-5) signalling, a member of the TGF-beta superfamily, is strongly linked to skeletal malformation. GDF-5-mediated signal transduction involves both BMP type I receptors, BMPR-IA and BMPR-IB. However, mutations in either GDF-5 or BMPR-IB lead to similar phenotypes, indicating that in chondrogenesis GDF-5 signalling seems to be exclusively mediated through BMPR-IB. Here, we present structural insights into the GDF-5: BMPR-IB complex revealing how binding specificity for BMPR-IB is generated on a molecular level. In BMPR-IB, a loop within the ligand-binding epitope functions similar to a latch allowing high-affinity binding of GDF-5. In BMPR-IA, this latch is in a closed conformation leading to steric repulsion. The new structural data now provide also a molecular basis of how phenotypically relevant missense mutations in GDF-5 might impair receptor binding and activation.