Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway.
Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway.
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扭曲胃结构的结构表征为BMP信号通路上相对功能提供了见解。
DOI：
10.1016/j.matbio.2016.01.019
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发表时间：
2016-09
期刊：
影响因子：
6.9
通讯作者：
Baldock, Clair
中科院分区：
文献类型：
--
作者：
Troilo, Helen;Barrett, Anne L.;Zuk, Alexandra V.;Lockhart-Cairns, Michael P.;Wohl, Alexander P.;Bayley, Christopher P.;Dajani, Rana;Tunnicliffe, Richard B.;Green, Lewis;Jowitt, Thomas A.;Sengle, Gerhard;Baldock, Clair
扭曲原肠形成(TSG)和Chordin是一种分泌的糖蛋白，它们共同发挥BMP(骨形态发生蛋白)拮抗剂的功能，调节BMP生长因子信号。Chordin与BMP结合，阻止它们与其受体相互作用，TSG已知能加强这一抑制复合体。TSG还作为BMP激动剂，通过促进Tolloid家族蛋白酶对Chordin的切割而发挥作用。在这里，我们探索了TSG发挥这一双重活动的结构机制。我们用溶液中生物分子分析表征了人TSG的纳米结构，表明TSG是一个扁平的十字形状的球形单体。TSG含有很高比例的N-连接多糖，与其分子量有关，这支持了其在溶解BMPs方面的作用。TSG与Chordin的C-末端区域有很高的亲和力，也能直接抑制BMP-7信号，但对BMP-4信号没有影响。尽管TSG和哺乳动物Tolloid都参与了Chordin切割，但利用表面等离子体共振技术无法检测到它们之间的相互作用。总之，这些数据表明，TSG通过诱导Chordin的构象变化而发挥BMP激动剂的作用，使其更容易被Tolloid切割，并作为BMP拮抗剂独立地或通过Chordin介导的机制发挥作用。在Tolloid单独切割Chordin后，TSG继续加强抑制复合体，支持部分切割的Chordin在BMP调节中的作用。
Twisted gastrulation (Tsg) and chordin are secreted glycoproteins that function together as BMP (bone morphogenetic protein) antagonists to regulate BMP growth factor signalling. Chordin binds to BMPs, preventing them from interacting with their receptors and Tsg is known to strengthen this inhibitory complex. Tsg also acts as a BMP agonist by promoting cleavage of chordin by tolloid-family proteinases. Here we explore the structural mechanism through which Tsg exerts this dual activity. We have characterized the nanoscale structure of human Tsg using in-solution biomolecular analysis and show that Tsg is a globular monomer with a flattened cross shape. Tsg has a high proportion of N-linked glycans, in relation to its molecular weight, which supports a role in solubilising BMPs. Tsg binds with high affinity to the C-terminal region of chordin and was also able to inhibit BMP-7 signalling directly but did not have an effect on BMP-4 signalling. Although both Tsg and mammalian tolloid are involved in chordin cleavage, no interaction could be detected between them using surface plasmon resonance. Together these data suggest that Tsg functions as a BMP-agonist by inducing conformational change in chordin making it more susceptible to tolloid cleavage and as a BMP-antagonist either independently or via a chordin-mediated mechanism. Following single cleavage of chordin by tolloids, Tsg continues to strengthen the inhibitory complex, supporting a role for partially cleaved chordin in BMP regulation.
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影响因子：
3.9
作者：
Troilo H;Barrett AL;Wohl AP;Jowitt TA;Collins RF;Bayley CP;Zuk AV;Sengle G;Baldock C
通讯作者：
Baldock C
影响因子：
3.4
作者：
Schuck, P
通讯作者：
Schuck, P
影响因子：
6.1
作者：
Konarev, PV;Volkov, VV;Svergun, DI
通讯作者：
Svergun, DI
影响因子：
3.4
作者：
Svergun, DI
通讯作者：
Svergun, DI
影响因子：
4.6
作者：
Blitz, IL;Cho, KWY;Chang, CB
通讯作者：
Chang, CB