Structure and activation of pro-activin A
Structure and activation of pro-activin A
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DOI：
10.1038/ncomms12052
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发表时间：
2016-07-01
影响因子：
16.6
通讯作者：
Hyvonen, Marko
中科院分区：
文献类型：
--
作者：
Wang, Xuelu;Fischer, Gerhard;Hyvonen, Marko
激活素是在发育和稳态中具有多种作用的生长因子。与所有TGF-β家族的生长因子一样，激活素合成为大的前体，成熟的二聚体生长因子从其蛋白水解释放。在这里，我们研究了激活素A的激活，并确定了未加工的前体和切割的前成熟复合物的晶体结构。用HRV 3C蛋白酶位点替换天然弗林蛋白酶切割位点，我们展示了蛋白质如何在蛋白水解后获得其生物活性，并且与分离的成熟结构域一样活跃。该复合物在用于生化分析的条件下保持结合，解离常数为5 nM，但前结构域可以被滤泡素抑制素从复合物中主动置换。我们的前激活素A的高分辨率结构与前TGF-β 1和前BMP-9结构中的特征相同，但揭示了一种新的寡聚体排列，二聚体蛋白中的原聚体具有结构域交换的交叉臂构象。
Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-beta family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-beta 1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein.