SHP2 is a tyrosine phosphatase that plays a regulatory role in multiple intracellular signaling cascades and is known to be oncogenic in certain contexts. In the absence of effectors, SHP2 adopts an autoinhibited conformation with its N-SH2 domain blocking the active site. Given the key role of N-SH2 in regulating SHP2, this domain has been extensively studied, often by X-ray crystallography. Using a combination of structural analyses and molecular dynamics (MD) simulations we show that the crystallographic environment can significantly influence the structure of the isolated N-SH2 domain, resulting in misleading interpretations. As an orthogonal method to X-ray crystallography, we use a combination of NMR spectroscopy and MD simulations to accurately determine the conformation of apo N-SH2 in solution. In contrast to earlier reports based on crystallographic data, our results indicate that apo N-SH2 in solution primarily adopts a conformation with a fully zipped central β-sheet, and that partial unzipping of this β-sheet is promoted by binding of either phosphopeptides or even phosphate/sulfate ions.

中文翻译：

---

磷酸肽与酪氨酸磷酸酶 SHP2 的 N-SH2 结构域的结合与其中央 β-折叠的解链相关

SHP2 是一种酪氨酸磷酸酶，在多种细胞内信号级联中发挥调节作用，并且已知在某些情况下具有致癌性。在没有效应子的情况下，SHP2 采用自抑制构象，其 N-SH2 结构域阻断活性位点。鉴于 N-SH2 在调节 SHP2 中的关键作用，该结构域已被广泛研究，通常通过 X 射线晶体学进行。通过结合结构分析和分子动力学 (MD) 模拟，我们发现晶体环境可以显着影响孤立的 N-SH2 结构域的结构，从而导致误导性的解释。作为 X 射线晶体学的正交方法，我们结合 NMR 波谱和 MD 模拟来准确确定溶液中 apo N-SH2 的构象。与早期基于晶体学数据的报告相比，我们的结果表明，溶液中的apo N-SH2主要采用具有完全拉链的中央β-折叠的构象，并且通过磷酸肽或磷酸肽的结合促进该β-折叠的部分解开。甚至磷酸根/硫酸根离子。