小柯机器人

德国哥廷根乔治奥古斯特大学Kai Tittmann研究组取得一项新突破。他们发现带有NOS桥的赖氨酸-半胱氨酸具有氧化还原开关调节酶的功能。这一研究成果发表在2021年5月5日出版的国际学术期刊《自然》杂志上。

他们报告发现一个带有NOS桥半胱氨酸和赖氨酸残基之间的共价交联，该桥在淋病奈瑟氏球菌（引起淋病的病原体）的转醛醇酶中用作变构氧化还原开关。对处于氧化和还原状态的蛋白质进行的X射线结构分析揭示了一种加载弹簧机制，该机制涉及氧化还原激活时的结构弛豫，该弛豫从蛋白质表面的变构氧化还原开关传播到蛋白质内部的活性位点。这种松弛导致关键催化残基的重新配置，并引起酶活性增加几个数量级。氧化还原开关在奈瑟菌科其他成员的相关转醛酶中高度保守。

例如，它存在于脑膜炎奈瑟菌的转醛酶中（一种病原体，是儿童脑膜炎和败血病的主要原因）。他们对蛋白质数据库进行了调查，发现NOS桥存在于生活的所有领域（包括智人）的不同蛋白质家族中，并且它通常位于催化或调控热点。他们的发现将为蛋白质和多肽的设计策略，以及针对赖氨酸-半胱氨酸氧化还原开关的新型药物和抗体的开发提供参考。

据介绍，半胱氨酸残基之间的二硫键是蛋白质中重要的翻译后修饰，对蛋白质的结构和稳定性具有至关重要的作用，这是控制蛋白质功能的酶或变构氧化还原开关中的氧化还原活性催化基团。除了形成二硫键外，半胱氨酸残基还容易被活性氧氧化，因此不仅是清除这些半胱氨酸的中心，而且在生物学以及病理学背景下，它们对细胞信号传导和通讯都是至关重要的。氧化的半胱氨酸具有很高的反应活性，并可能与某些酪氨酸在某些氧化还原酶的活性位点上形成共价共轭物。然而，以前没有证明具有带有二硫键以外的共价交联键的调节开关。

附：英文原文

Title: A lysine–cysteine redox switch with an NOS bridge regulates enzyme function

Author: Marie Wensien, Fabian Rabe von Pappenheim, Lisa-Marie Funk, Patrick Kloskowski, Ute Curth, Ulf Diederichsen, Jon Uranga, Jin Ye, Pan Fang, Kuan-Ting Pan, Henning Urlaub, Ricardo A. Mata, Viktor Sautner, Kai Tittmann

Issue&Volume: 2021-05-05

Abstract: Disulfide bonds between cysteine residues are important post-translational modifications in proteins that have critical roles for protein structure and stability, as redox-active catalytic groups in enzymes or allosteric redox switches that govern protein function1,2,3,4. In addition to forming disulfide bridges, cysteine residues are susceptible to oxidation by reactive oxygen species, and are thus central not only to the scavenging of these but also to cellular signalling and communication in biological as well as pathological contexts5,6. Oxidized cysteine species are highly reactive and may form covalent conjugates with, for example, tyrosines in the active sites of some redox enzymes7,8. However, to our knowledge, regulatory switches with covalent crosslinks other than disulfides have not previously been demonstrated. Here we report the discovery of a covalent crosslink between a cysteine and a lysine residue with a NOS bridge that serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, the pathogen that causes gonorrhoea. X-ray structure analysis of the protein in the oxidized and reduced state reveals a loaded-spring mechanism that involves a structural relaxation upon redox activation, which is propagated from the allosteric redox switch at the protein surface to the active site in the protein interior. This relaxation leads to a reconfiguration of key catalytic residues and elicits an increase in enzymatic activity of several orders of magnitude. The redox switch is highly conserved in related transaldolases from other members of the Neisseriaceae; for example, it is present in the transaldolase of Neisseria meningitides (a pathogen that is the primary cause of meningitis and septicaemia in children). We surveyed the Protein Data Bank and found that the NOS bridge exists in diverse protein families across all domains of life (including Homo sapiens) and that it is often located at catalytic or regulatory hotspots. Our findings will inform strategies for the design of proteins and peptides, as well as the development of new classes of drugs and antibodies that target the lysine–cysteine redox switch9,10.

DOI: 10.1038/s41586-021-03513-3

Source: https://www.nature.com/articles/s41586-021-03513-3

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