Huculeci Radu, Cilia Elisa, Lyczek Agatha, Buts Lieven, Houben Klaartje, Seeliger Markus A, van Nuland Nico, Lenaerts Tom
Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussel, Belgium.
MLG, Départment d'Informatique, Université Libre de Bruxelles, Boulevard du Triomphe CP212, 1050 Brussels, Belgium; Interuniversity Institute of Bioinformatics Brussels (IB(2)), ULB-VUB, La Plaine Campus, Boulevard du Triomphe CP 263, 1050 Brussels, Belgium.
Structure. 2016 Nov 1;24(11):1947-1959. doi: 10.1016/j.str.2016.08.016. Epub 2016 Sep 29.
Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information. We reveal that binding the phosphorylated tail of Fyn perturbs a residue cluster near the linker connecting the SH2 and SH3 domains of Fyn, which is known to be relevant in the regulation of the activity of Fyn. Biochemical perturbation experiments validate that those residues are essential for inhibition of Fyn, leading to a gain of function upon mutation. These findings reveal how side-chain dynamics may facilitate the allosteric regulation of the different members of the Src kinase family.
Src激酶活性受多种机制控制，这些机制涉及激酶和调节结构域的协同运动。尽管对主链动力学已有广泛了解，但对于调节结构域内更细微的侧链动力学及其在激活过程中的作用却知之甚少。在这里，我们通过实验性甲基动力学结果以及预测的侧链构象偶联变化表明，Fyn的SH2结构包含一个能够传递结合信息的动态网络。我们发现，结合Fyn的磷酸化尾部会扰乱Fyn的SH2和SH3结构域连接区附近的一个残基簇，已知该残基簇与Fyn活性调节相关。生化扰动实验证实，这些残基对于抑制Fyn至关重要，突变后会导致功能获得。这些发现揭示了侧链动力学如何促进Src激酶家族不同成员的变构调节。
