Ge Gaoxiang, Hopkins Delana R, Ho Wen-Bin, Greenspan Daniel S
Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Mol Cell Biol. 2005 Jul;25(14):5846-58. doi: 10.1128/MCB.25.14.5846-5858.2005.
All transforming growth factor beta (TGF-beta) superfamily members are synthesized as precursors with prodomain sequences that are proteolytically removed by subtilisin-like proprotein convertases (SPCs). For most superfamily members, this is believed sufficient for activation. Exceptions are TGF-betas 1 to 3 and growth differentiation factor 8 (GDF8), also known as myostatin, which form noncovalent, latent complexes with their SPC-cleaved prodomains. Sequence similarities between TGF-betas 1 to 3, myostatin, and superfamily member GDF11, also known as bone morphogenetic protein 11 (BMP11), prompted us to examine whether GDF11 might be capable of forming a latent complex with its cleaved prodomain. Here we demonstrate that GDF11 forms a noncovalent latent complex with its SPC-cleaved prodomain and that this latent complex is activated via cleavage at a single specific site by members of the developmentally important BMP1/Tolloid family of metalloproteinases. Evidence is provided for a molecular model whereby formation and activation of this complex may play a general role in modulating neural differentiation. In particular, mutant GDF11 prodomains impervious to cleavage by BMP1/Tolloid proteinases are shown to be potent stimulators of neurodifferentiation, with potential for therapeutic applications.
所有转化生长因子β（TGF-β）超家族成员均以前体形式合成，其前结构域序列被枯草杆菌蛋白酶样前蛋白转化酶（SPCs）通过蛋白水解作用去除。对于大多数超家族成员而言，人们认为这足以实现激活。例外情况是TGF-β1至3以及生长分化因子8（GDF8，也称为肌抑素），它们与其经SPC切割的前结构域形成非共价的潜伏复合物。TGF-β1至3、肌抑素与超家族成员GDF11（也称为骨形态发生蛋白11，即BMP11）之间的序列相似性促使我们研究GDF11是否能够与其切割后的前结构域形成潜伏复合物。在此我们证明，GDF11与其经SPC切割的前结构域形成非共价潜伏复合物，并且该潜伏复合物通过发育上重要的金属蛋白酶BMP1/Tolloid家族成员在单个特定位点的切割而被激活。我们提供了一个分子模型的证据，据此该复合物的形成和激活可能在调节神经分化中发挥普遍作用。特别是，对BMP1/Tolloid蛋白酶切割具有抗性的突变型GDF11前结构域被证明是神经分化的有效刺激剂，具有潜在的治疗应用价值。
