Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, Austin, TX 78712, USA.
Int J Mol Sci. 2022 Aug 4;23(15):8679. doi: 10.3390/ijms23158679.
Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate several signaling branches, including mitogen-activated protein kinase cascades. Arrestin-3-dependent activation of the JNK family can be recapitulated with peptide fragments, which are monofunctional elements distilled from this multi-functional arrestin protein. Here, we use maltose-binding protein fusions of arrestin-3-derived peptides to identify arrestin elements that bind kinases of the ASK1-MKK4/7-JNK3 cascade and the shortest peptide facilitating JNK signaling. We identified a 16-residue arrestin-3-derived peptide expressed as a Venus fusion that leads to activation of JNK3α2 in cells. The strength of the binding to the kinases does not correlate with peptide activity. The ASK1-MKK4/7-JNK3 cascade has been implicated in neuronal apoptosis. While inhibitors of MAP kinases exist, short peptides are the first small molecule tools that can activate MAP kinases.
抑制蛋白最初是作为 G 蛋白偶联受体 G 蛋白介导信号的抑制剂被发现的。后来的研究表明，抑制蛋白也可以启动几个信号通路，包括丝裂原活化蛋白激酶（MAPK）级联反应。用肽片段可以重现 arrestin-3 依赖性 JNK 家族的激活，这些肽片段是从这种多功能抑制蛋白中提取的单功能元件。在这里，我们使用麦芽糖结合蛋白融合的 arrestin-3 衍生肽来鉴定与 ASK1-MKK4/7-JNK3 级联反应的激酶以及促进 JNK 信号传导的最短肽结合的抑制蛋白元件。我们鉴定出一种由 Venus 融合表达的 16 个残基的 arrestin-3 衍生肽，该肽在细胞中导致 JNK3α2 的激活。与激酶的结合强度与肽活性不相关。ASK1-MKK4/7-JNK3 级联反应已被牵连到神经元凋亡中。虽然存在 MAP 激酶抑制剂，但短肽是第一种可以激活 MAP 激酶的小分子工具。
