Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA
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...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54607-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850129074965446656 |
|---|---|
| author | Zhenyu Ma Sue C. Nang Zhuo Liu Jingyi Zhu Kaijie Mu Limei Xu Min Xiao Lushan Wang Jian Li Xukai Jiang |
| author_facet | Zhenyu Ma Sue C. Nang Zhuo Liu Jingyi Zhu Kaijie Mu Limei Xu Min Xiao Lushan Wang Jian Li Xukai Jiang |
| author_sort | Zhenyu Ma |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-608edd1a23834dcfb0d75f0ae88e8a0d |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-608edd1a23834dcfb0d75f0ae88e8a0d2025-08-20T02:33:06ZengNature PortfolioNature Communications2041-17232024-11-0115111410.1038/s41467-024-54607-1Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptAZhenyu Ma0Sue C. Nang1Zhuo Liu2Jingyi Zhu3Kaijie Mu4Limei Xu5Min Xiao6Lushan Wang7Jian Li8Xukai Jiang9National Glycoengineering Research Center, Shandong UniversityBiomedicine Discovery Institute, Monash UniversityNational Glycoengineering Research Center, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityBiomedicine Discovery Institute, Monash UniversityState Key Laboratory of Microbial Technology, Shandong UniversityNational Glycoengineering Research Center, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityBiomedicine Discovery Institute, Monash UniversityNational Glycoengineering Research Center, Shandong UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54607-1 |
| spellingShingle | Zhenyu Ma Sue C. Nang Zhuo Liu Jingyi Zhu Kaijie Mu Limei Xu Min Xiao Lushan Wang Jian Li Xukai Jiang Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA Nature Communications |
| title | Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA |
| title_full | Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA |
| title_fullStr | Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA |
| title_full_unstemmed | Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA |
| title_short | Membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase EptA |
| title_sort | membrane lipid homeostasis dually regulates conformational transition of phosphoethanolamine transferase epta |
| url | https://doi.org/10.1038/s41467-024-54607-1 |
| work_keys_str_mv | AT zhenyuma membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT suecnang membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT zhuoliu membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT jingyizhu membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT kaijiemu membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT limeixu membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT minxiao membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT lushanwang membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT jianli membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta AT xukaijiang membranelipidhomeostasisduallyregulatesconformationaltransitionofphosphoethanolaminetransferaseepta |