Program in Cellular and Molecular Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2023 Jun 13;120(24):e2304874120. doi: 10.1073/pnas.2304874120. Epub 2023 Jun 6.
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.
潜伏转化生长因子-β2（TGF-β2）的激活机制尚未完全阐明。与 TGF-β1 和 β3 不同，TGF-β2 前肽缺乏七残基 RGDLXX（L/I）整联蛋白识别基序，且不被整联蛋白激活。在这里，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 残基整联蛋白识别基序（YTSGDQKTIKSTR），使其专门被整合素 αVβ6 激活，而不是 αVβ8。这两类基序竞争 αVβ6 中的同一结合位点。较长基序中的多种变化使其具有特异性。ProTGF-β2 结构定义了与 ProTGF-β1 的有趣差异，以及与 αVβ6 激活的结构背景。ProTGF-β2 也存在一些独立于整联蛋白的激活，而 ProTGF-β3 更是如此。我们的发现对临床试验中纤维化的 αVβ6 治疗具有重要意义，因为此前并未预期 TGF-β2 激活的抑制作用。
