Volume 26, No 12, Dec 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 12, December 2016: 1330-1344 | Open Access
ORIGINAL ARTICLES
Crystal structure of FabZ-ACP complex reveals a dynamic seesaw-like catalytic mechanism of dehydratase in fatty acid biosynthesis
Lin Zhang1,2, Jianfeng Xiao3, Jianrong Xu1, Tianran Fu1, Zhiwei Cao1, Liang Zhu1,2, Hong-Zhuan Chen1,2, Xu Shen3, Hualiang Jiang3 and Liang Zhang1,2
1Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai, China
3State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence: Liang Zhang,(liangzhang2014@sjtu.edu.cn)
Fatty acid biosynthesis (FAS) is a vital process in cells. Fatty acids are essential for cell assembly and cellular metabolism. Abnormal FAS directly correlates with cell growth delay and human diseases, such as metabolic syndromes and various cancers. The FAS system utilizes an acyl carrier protein (ACP) as a transporter to stabilize and shuttle the growing fatty acid chain throughout enzymatic modules for stepwise catalysis. Studying the interactions between enzymatic modules and ACP is, therefore, critical for understanding the biological function of the FAS system. However, the information remains unclear due to the high flexibility of ACP and its weak interaction with enzymatic modules. We present here a 2.55 Å crystal structure of type II FAS dehydratase FabZ in complex with holo-ACP, which exhibits a highly symmetrical FabZ hexamer-ACP3 stoichiometry with each ACP binding to a FabZ dimer subunit. Further structural analysis, together with biophysical and computational results, reveals a novel dynamic seesaw-like ACP binding and catalysis mechanism for the dehydratase module in the FAS system, which is regulated by a critical gatekeeper residue (Tyr100 in FabZ) that manipulates the movements of the β-sheet layer. These findings improve the general understanding of the dehydration process in the FAS system and will potentially facilitate drug and therapeutic design for diseases associated with abnormalities in FAS.
10.1038/cr.2016.136
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