Heidelberg Institute for Theoretical Studies (HITS), Heidelberg University, Heidelberg, Germany.
Institute for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
Elife. 2023 Oct 16;12:e85216. doi: 10.7554/eLife.85216.
c-Abl kinase, a key signaling hub in many biological processes ranging from cell development to proliferation, is tightly regulated by two inhibitory Src homology domains. An N-terminal myristoyl modification can bind to a hydrophobic pocket in the kinase C-lobe, which stabilizes the autoinhibitory assembly. Activation is triggered by myristoyl release. We used molecular dynamics simulations to show how both myristoyl and the Src homology domains are required to impose the full inhibitory effect on the kinase domain and reveal the allosteric transmission pathway at residue-level resolution. Importantly, we find myristoyl insertion into a membrane to thermodynamically compete with binding to c-Abl. Myristoyl thus not only localizes the protein to the cellular membrane, but membrane attachment at the same time enhances activation of c-Abl by stabilizing its preactivated state. Our data put forward a model in which lipidation tightly couples kinase localization and regulation, a scheme that currently appears to be unique for this non-receptor tyrosine kinase.
c-Abl 激酶是许多生物学过程中的关键信号枢纽，从细胞发育到增殖都有涉及，它受到两个抑制性Src 同源结构域的严格调控。N 端豆蔻酰化修饰可以与激酶 C 结构域中的疏水口袋结合，从而稳定自抑制组装。激活是通过豆蔻酰基释放触发的。我们使用分子动力学模拟表明，豆蔻酰基和 Src 同源结构域都需要对激酶结构域施加完全的抑制作用，并揭示了在残基分辨率水平上的变构传递途径。重要的是，我们发现豆蔻酰基插入膜中会与 c-Abl 结合产生热力学竞争。因此，豆蔻酰基不仅将蛋白质定位在细胞膜上，而且通过稳定其预激活状态，同时增强 c-Abl 的激活。我们的数据提出了一个模型，其中脂质化将激酶定位和调节紧密结合在一起，这种方案目前似乎对这种非受体酪氨酸激酶是独特的。
