Lin Lirui, Zou Haiying, Li Wenjin, Xu Li-Yan, Li En-Min, Dong Geng
Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China.
Medical Informatics Research Center, Shantou University Medical College, Shantou, China.
Front Chem. 2021 Dec 14;9:797036. doi: 10.3389/fchem.2021.797036. eCollection 2021.
Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes the oxidative deamination ε-amino group of lysine. It is found that LOXL2 is a promotor for the metastasis and invasion of cancer cells. Disulfide bonds are important components in LOXL2, and they play a stabilizing role for protein structure or a functional role for regulating protein bioactivity. The redox potential of disulfide bond is one important property to determine the functional role of disulfide bond. In this study, we have calculated the reduction potential of all the disulfide bonds in LOXL2 by non-equilibrium alchemical simulations. Our results show that seven of seventeen disulfide bonds have high redox potentials between -182 and -298 mV and could have a functional role, viz., Cys573-Cys625, Cys579-Cys695, Cys657-Cys673, and Cys663-Cys685 in the catalytic domain, Cys351-Cys414, Cys464-Cys530, and Cys477-Cys543 in the scavenger receptor cysteine-rich (SRCR) domains. The disulfide bond of Cys351-Cys414 is predicted to play an allosteric function role, which could affect the metastasis and invasion of cancer cells. Other functional bonds have a catalytic role related to enzyme activity. The rest of disulfide bonds are predicted to play a structural role. Our study provides an important insight for the classification of disulfide bonds in LOXL2 and can be utilized for the drug design that targets the cysteine residues in LOXL2.
赖氨酰氧化酶样2（LOXL2）是一种催化赖氨酸ε-氨基氧化脱氨的金属酶。研究发现LOXL2是癌细胞转移和侵袭的促进因子。二硫键是LOXL2的重要组成部分，它们对蛋白质结构起稳定作用或对调节蛋白质生物活性起功能作用。二硫键的氧化还原电位是决定其功能作用的一个重要性质。在本研究中，我们通过非平衡炼金术模拟计算了LOXL2中所有二硫键的还原电位。我们的结果表明，17个二硫键中有7个具有介于-182至-298 mV之间的高氧化还原电位，可能具有功能作用，即催化结构域中的Cys573-Cys625、Cys579-Cys695、Cys657-Cys673和Cys663-Cys685，富含半胱氨酸的清道夫受体（SRCR）结构域中的Cys351-Cys414、Cys464-Cys530和Cys477-Cys543。预测Cys351-Cys414的二硫键起变构功能作用，可能影响癌细胞的转移和侵袭。其他功能键具有与酶活性相关的催化作用。其余二硫键预计起结构作用。我们的研究为LOXL2中二硫键的分类提供了重要见解，可用于针对LOXL2中半胱氨酸残基的药物设计。
