PDF(Pubmed)
Abstract：
Activation of latent transforming growth factor (TGF)-β2 is incompletely understood. Unlike TGF-β1 and β3, the TGF-β2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-β2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin αVβ6 but not αVβ8. Both classes of motifs compete for the same binding site in αVβ6. Multiple changes in the longer motif underlie its specificity. ProTGF-β2 structures define interesting differences from proTGF-β1 and the structural context for activation by αVβ6. Some integrin-independent activation is also seen for proTGF-β2 and even more so for proTGF-β3. Our findings have important implications for therapeutics to αVβ6 in clinical trials for fibrosis, in which inhibition of TGF-β2 activation has not been anticipated.
摘要：
潜在转化生长因子(TGF)-β2的活化尚未完全了解。与TGF-β1和β3不同，TGF-β2前结构域缺乏七个残基的RGDLXX（L/I）整联蛋白识别基序，并且被认为不会被整联蛋白激活。这里,我们报告了一个令人惊讶的发现，即TGF-β2含有一个相关但不同的13个残基的整合素识别基序（YTSGDQKTIKSTR），该基序专门用于通过整合素αVβ6而不是αVβ8激活。两类基序在αVβ6中竞争相同的结合位点。较长基序的多种变化是其特异性的基础。ProTGF-β2结构定义了与proTGF-β1的有趣差异以及αVβ6活化的结构背景。对于原TGF-β2也观察到一些不依赖整合素的激活,对于原TGF-β3甚至更多。我们的发现对纤维化临床试验中αVβ6的治疗具有重要意义。其中尚未预期抑制TGF-β2活化。
