Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA

Zhenyu Ma, Sue C. Nang, Zhuo Liu, Jingyi Zhu, Kaijie Mu, Limei Xu, Min Xiao, Lushan Wang, Jian Li () and Xukai Jiang ()
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Zhenyu Ma: Shandong University
Sue C. Nang: Monash University
Zhuo Liu: Shandong University
Jingyi Zhu: Shandong University
Kaijie Mu: Monash University
Limei Xu: Shandong University
Min Xiao: Shandong University
Lushan Wang: Shandong University
Jian Li: Monash University
Xukai Jiang: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The phosphoethanolamine transferase EptA utilizes phosphatidylethanolamine (PE) in the bacterial cell membrane to modify the structure of lipopolysaccharide, thereby conferring antimicrobial resistance on Gram-negative pathogens. Previous studies have indicated that excessive consumption of PE can disrupt the cell membrane, leading to cell death. This implies the presence of a regulatory mechanism for EptA catalysis to maintain a balance between antimicrobial resistance and bacterial growth. Through microsecond-scale all-atom molecular dynamics simulations, we demonstrate that membrane lipid homeostasis modulates the conformational transition and catalytic activation of EptA. The conformation of EptA oscillates between closed and open states, ensuring the precise spatiotemporal sequence of substrates binding. Interestingly, the conformation of EptA is significantly influenced by its surrounding lipid microenvironment, particularly the PE proportion in the membrane. PE-rich membrane conditions initiate and stabilize the open conformation of EptA through both orthosteric and allosteric effects. Importantly, the reaction mediated by EptA gradually depletes PE in the membrane, ultimately hindering its conformational transition and catalytic activation. These findings collectively establish a self-promoted model, illustrating the regulatory mechanism of EptA during the development of antibiotic resistance.

Date: 2024
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DOI: 10.1038/s41467-024-54607-1

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