A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8.
A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8.
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DOI：
10.1073/pnas.2304874120
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发表时间：
2023-06-13
影响因子：
11.1
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Le, Viet Q.;Zhao, Bo;Ramesh, Siddanth;Toohey, Cameron;DeCosta, Adam;Mintseris, Julian;Liu, Xinyue;Gygi, Steven;Springer, Timothy A.
转化生长因子（TGF）-β调节免疫功能、发育和组织修复。这三种TGF-β以无活性的潜伏形式产生，必须被激活以启动TGF-β信号传导。我们已经发现TGF-β2可以被整合素αVβ6激活。与TGF-β1和β3不同，TGF-β2由整合素αVβ6而不是αVβ8特异性激活。整合素αVβ6在TGF-β2活化中未被认识到的作用填补了我们对TGF-β生物学理解的巨大空白，并对开发安全有效的纤维化整合素αVβ6治疗剂具有重要意义，其中以前未考虑抑制TGF-β2活化。潜伏性转化生长因子（TGF）-β2的激活尚不完全清楚。与TGF-β1和β3不同，TGF-β2前结构域缺乏7个残基的RGDLXX（L/I）整联蛋白识别基序，并且被认为不被整联蛋白激活。在这里，我们报告了一个令人惊讶的发现，TGF-β2含有一个相关但不同的13残基整合素识别基序（YTSGDQKTIKSTR），该基序专门用于整合素αVβ6而不是αVβ8的激活。两类基序竞争αVβ6中的相同结合位点。较长基序的多重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激活的结构背景。对于proTGF-β2也观察到一些整合素非依赖性活化，对于proTGF-β3甚至更多。我们的研究结果对纤维化临床试验中αVβ6的治疗具有重要意义，其中TGF-β2活化的抑制作用尚未被预期。
Transforming growth factor (TGF)-β regulates immune function, development, and tissue repair. The three TGF-βs are produced in an inactive, latent form that must be activated to initiate TGF-β signaling. We have found that TGF-β2 can be activated by integrin αVβ6. Unlike TGF-β1 and β3, TGF-β2 is specifically activated by integrin αVβ6 and not αVβ8. The unappreciated role of integrin αVβ6 in TGF-β2 activation fills a large gap in our understanding of TGF-β biology and has important implications for the development of safe and efficacious integrin αVβ6 therapeutics for fibrosis in which inhibition of TGF-β2 activation had not previously been considered. 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.
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影响因子：
3.7
作者：
Kim JH;Lee SR;Li LH;Park HJ;Park JH;Lee KY;Kim MK;Shin BA;Choi SY
通讯作者：
Choi SY
影响因子：
7.2
作者：
Hinck AP;Mueller TD;Springer TA
通讯作者：
Springer TA
影响因子：
5.6
作者：
Dallas, SL;Zhao, S;Bonewald, LF
通讯作者：
Bonewald, LF
影响因子：
16.8
作者：
Dong, Xianchi;Hudson, Nathan E.;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
DOI：
10.1073/pnas.0404201101
发表时间：
2004-09-07
影响因子：
11.1
作者：
Artoni, A;Li, JH;Coller, BS
通讯作者：
Coller, BS