Shi Yu, Zang Ning, Lou Ningjie, Xu Yongchang, Sun Jingdu, Huang Man, Zhang Huimin, Lu Huijie, Zhou Chun, Feng Youjun
Departments of Microbiology and General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Department of Toxicology, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Sci Adv. 2022 Sep 2;8(35):eabq3944. doi: 10.1126/sciadv.abq3944.
and , two groups of major human pathogens, are equipped with a fatty acid kinase (Fak) machinery to scavenge host fatty acids. The Fak complex is contains an ATP-binding subunit FakA, which interacts with varied FakB isoforms, and synthesizes acyl-phosphate from extracellular fatty acids. However, how FakA recognizes its FakB partners and then activates different fatty acids is poorly understood. Here, we systematically describe the Fak system from the zoonotic pathogen, . The crystal structure of SsFakA complexed with SsFakB2 was determined at 2.6 Å resolution. An in vitro system of Fak-PlsX (phosphate: acyl-ACP transacylase) was developed to track acyl-phosphate intermediate and its final product acyl-ACP. Structure-guided mutagenesis enabled us to characterize a mechanism for streptococcal FakA working with FakB partners engaged in host fatty acid scavenging. These findings offer a comprehensive description of the Fak kinase machinery, thus advancing the discovery of attractive targets against deadly infections with .
两组主要的人类病原体都配备了脂肪酸激酶（Fak）机制来清除宿主脂肪酸。Fak复合物包含一个ATP结合亚基FakA，它与多种FakB同工型相互作用，并从细胞外脂肪酸合成酰基磷酸。然而，FakA如何识别其FakB伙伴并激活不同脂肪酸的机制却知之甚少。在这里，我们系统地描述了来自人畜共患病原体的Fak系统。SsFakA与SsFakB2复合的晶体结构在2.6 Å分辨率下确定。开发了Fak-PlsX（磷酸：酰基-ACP转酰基酶）体外系统来追踪酰基磷酸中间体及其最终产物酰基-ACP。基于结构的诱变使我们能够表征链球菌FakA与参与宿主脂肪酸清除的FakB伙伴协同工作的机制。这些发现全面描述了Fak激酶机制，从而推动了针对由……引起的致命感染的有吸引力靶点的发现。
