Steven J. Jensen, Bonnie J. Cuthbert, Fernando Garza-Sánchez, Colette C. Helou, Rodger de Miranda, Celia W. Goulding, Christopher S. Hayes
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引用次数: 0
摘要
高级糖化终产物(AGE)是一种普遍存在的蛋白质损伤形式,与神经退行性疾病、动脉粥样硬化和糖尿病的发病机制有关。糖化通常由活性二羰基化合物介导,这些化合物作为葡萄糖代谢的有毒副产品在所有细胞中积累。在这里,我们发现 AGE 交联可激活一种抗菌磷脂酶效应蛋白,这种蛋白由泄殖腔肠杆菌的 VI 型分泌系统调配。内源性甲基乙二醛会与特定的精氨酸-赖氨酸对发生反应,从而拴住磷脂酶结构域的 N 端和 C 端 α-螺旋。在这些位置进行置换后,交联作用和毒性磷脂酶活性都会减弱,但体外酶功能可以通过共价连接 N 端和 C 端的工程二硫化物来恢复。因此,AGE 交联是一种真正的翻译后修饰,可以稳定磷脂酶的结构。鉴于甲基乙二酸在原核和真核细胞中无处不在,这些研究结果表明,糖化可被更广泛地用于稳定其他蛋白质。这种强化三级结构的替代策略在细胞质中可能特别有利,因为在细胞质中氧化还原电位阻碍了二硫键的形成。
Advanced glycation end-product crosslinking activates a type VI secretion system phospholipase effector protein
Advanced glycation end-products (AGE) are a pervasive form of protein damage implicated in the pathogenesis of neurodegenerative disease, atherosclerosis and diabetes mellitus. Glycation is typically mediated by reactive dicarbonyl compounds that accumulate in all cells as toxic byproducts of glucose metabolism. Here, we show that AGE crosslinking is harnessed to activate an antibacterial phospholipase effector protein deployed by the type VI secretion system of Enterobacter cloacae. Endogenous methylglyoxal reacts with a specific arginine-lysine pair to tether the N- and C-terminal α-helices of the phospholipase domain. Substitutions at these positions abrogate both crosslinking and toxic phospholipase activity, but in vitro enzyme function can be restored with an engineered disulfide that covalently links the N- and C-termini. Thus, AGE crosslinking serves as a bona fide post-translation modification to stabilize phospholipase structure. Given the ubiquity of methylglyoxal in prokaryotic and eukaryotic cells, these findings suggest that glycation may be exploited more generally to stabilize other proteins. This alternative strategy to fortify tertiary structure could be particularly advantageous in the cytoplasm, where redox potentials preclude disulfide bond formation.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.