用于光学控制的工程 SHP2 磷酸酶,Biochemistry

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用于光学控制的工程 SHP2 磷酸酶
Biochemistry ( IF 2.9 ) Pub Date : 2022-11-08 , DOI: 10.1021/acs.biochem.2c00387
Amy Ryan ₁ , Chasity P Janosko ₁ , Taylor M Courtney ₁ , Alexander Deiters ₁

Affiliation

信号转导通路负责维持细胞功能，包括增殖、分化、凋亡和细胞周期进程。这些途径通过蛋白激酶传播磷酸化信号以及蛋白磷酸酶去除磷酸化信号来维持。根据上下文，翻译后修饰可能对信号通路产生积极或消极的影响。正向和负向调节器的复杂网络为细胞信号传导机制的剖析提供了一个具有挑战性的目标，特别是关于通过磷酸酶对信号转导的更微妙的抑制。我们报告了两种用于复杂磷酸酶光学控制的互补方法的开发：包含 SH2 结构域的蛋白酪氨酸磷酸酶 2 (SHP2)。我们研究了通过 (1) 位点特异性掺入笼状酪氨酸以光激活催化活性以控制必需的底物结合残基和 (2) 位点特异性掺入笼状赖氨酸在保守区域控制 SHP2 的催化功能用于控制 SHP2 结合伙伴对接位点的变构口袋内的残基。这些方法可推广到带有蛋白酪氨酸磷酸酶 (PTP) 催化结构域或 SH2 结构域的蛋白质，包括 SHP1、PTP 家族磷酸酶和各种包含 SH2 结构域的蛋白质。

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Engineering SHP2 Phosphatase for Optical Control

Signal transduction pathways are responsible for maintaining cellular functions, including proliferation, differentiation, apoptosis, and cell cycle progression. These pathways are maintained through the propagation of phosphorylation signals by protein kinases, as well as the removal of phosphorylation signals by protein phosphatases. Depending on the context, post-translational modification could have either a positive or negative effect on a signaling pathway. Intricate networks of positive and negative regulators offer a challenging target for the dissection of cell signaling mechanisms, particularly regarding the more subtle dampening of signal transduction through phosphatases. We report the development of two complimentary methods for the optical control of a complex phosphatase: SH2 domain-containing protein tyrosine phosphatase-2 (SHP2). We investigated controlling the catalytic function of SHP2 through (1) site-specific incorporation of a caged tyrosine for light activation of catalytic activity for the control of an essential substrate binding residue and (2) site-specific incorporation of a caged lysine at a conserved residue within an allosteric pocket for the control of SHP2 binding partner docking sites. These methods are generalizable to proteins bearing either a protein tyrosine phosphatase (PTP) catalytic domain or an SH2 domain, including SHP1, PTP family phosphatases, and a diverse range of SH2 domain-containing proteins.

更新日期：2022-11-08

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