Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex
ABSTRACT Mycobacterium tuberculosis, the causative agent of the airborne infection tuberculosis (TB), contains 13 mycobacterial membrane protein large (MmpL) transporters that can be divided into two distinct subclasses. These MmpL proteins play important functional roles within the mycobacterium an...
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American Society for Microbiology
2024-12-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03035-24 |
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| author | Rakesh Maharjan Zhemin Zhang Philip A. Klenotic William D. Gregor Georgiana E. Purdy Edward W. Yu |
| author_facet | Rakesh Maharjan Zhemin Zhang Philip A. Klenotic William D. Gregor Georgiana E. Purdy Edward W. Yu |
| author_sort | Rakesh Maharjan |
| collection | DOAJ |
| description | ABSTRACT Mycobacterium tuberculosis, the causative agent of the airborne infection tuberculosis (TB), contains 13 mycobacterial membrane protein large (MmpL) transporters that can be divided into two distinct subclasses. These MmpL proteins play important functional roles within the mycobacterium and subsequently are considered attractive drug targets to combat TB infection. Previously, we reported both X-ray and cryo-electron microscopy (cryo-EM) structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Thus far, there is no structural information available for the other subclass, which includes MmpL5, an inner membrane transporter that plays a critical role in iron hemostasis. Here, we report the first cryo-EM structure of the Mycobacterium smegmatis MmpL5 transporter bound with the meromycolate extension acyl carrier protein M (AcpM) to a resolution of 2.81 Å. Our structural data reveals that MmpL5 and AcpM interact in the cytoplasm to form a complex, and this allows us to propose that MmpL5 may also associate with the mycobactin L (MbtL) protein in a similar fashion to form a heterocomplex important for iron acquisition, which enables the survival and replication of the mycobacterium.IMPORTANCEThe emergence and spread of multidrug-resistant tuberculosis (TB) present enormous challenges to the global public health. The causative agent, Mycobacterium tuberculosis, has now infected more than one-third of the world's population. Here, we report the first structure of the mycobacterial membrane protein large 5 (MmpL5), an essential transporter for iron acquisition, bound with the meromycolate extension acyl carrier protein M (AcpM), indicating a plausible pathway for mycobactin translocation. Our studies will ultimately inform an era in structure-guided drug design to combat TB infection. |
| format | Article |
| id | doaj-art-21c5aa30ccdd47e085f99cbabfb58f76 |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-21c5aa30ccdd47e085f99cbabfb58f762025-08-20T01:58:59ZengAmerican Society for MicrobiologymBio2150-75112024-12-01151210.1128/mbio.03035-24Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complexRakesh Maharjan0Zhemin Zhang1Philip A. Klenotic2William D. Gregor3Georgiana E. Purdy4Edward W. Yu5Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USADepartment of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USADepartment of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USADepartment of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USADepartment of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USADepartment of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USAABSTRACT Mycobacterium tuberculosis, the causative agent of the airborne infection tuberculosis (TB), contains 13 mycobacterial membrane protein large (MmpL) transporters that can be divided into two distinct subclasses. These MmpL proteins play important functional roles within the mycobacterium and subsequently are considered attractive drug targets to combat TB infection. Previously, we reported both X-ray and cryo-electron microscopy (cryo-EM) structures of the MmpL3 transporter, providing high-resolution structural information for this subclass of the MmpL proteins. Thus far, there is no structural information available for the other subclass, which includes MmpL5, an inner membrane transporter that plays a critical role in iron hemostasis. Here, we report the first cryo-EM structure of the Mycobacterium smegmatis MmpL5 transporter bound with the meromycolate extension acyl carrier protein M (AcpM) to a resolution of 2.81 Å. Our structural data reveals that MmpL5 and AcpM interact in the cytoplasm to form a complex, and this allows us to propose that MmpL5 may also associate with the mycobactin L (MbtL) protein in a similar fashion to form a heterocomplex important for iron acquisition, which enables the survival and replication of the mycobacterium.IMPORTANCEThe emergence and spread of multidrug-resistant tuberculosis (TB) present enormous challenges to the global public health. The causative agent, Mycobacterium tuberculosis, has now infected more than one-third of the world's population. Here, we report the first structure of the mycobacterial membrane protein large 5 (MmpL5), an essential transporter for iron acquisition, bound with the meromycolate extension acyl carrier protein M (AcpM), indicating a plausible pathway for mycobactin translocation. Our studies will ultimately inform an era in structure-guided drug design to combat TB infection.https://journals.asm.org/doi/10.1128/mbio.03035-24Mycobacterial membrane protein LargeMmpL5acyl carrier protein Mmycobactin Lsiderophore exportiron acquisition |
| spellingShingle | Rakesh Maharjan Zhemin Zhang Philip A. Klenotic William D. Gregor Georgiana E. Purdy Edward W. Yu Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex mBio Mycobacterial membrane protein Large MmpL5 acyl carrier protein M mycobactin L siderophore export iron acquisition |
| title | Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex |
| title_full | Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex |
| title_fullStr | Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex |
| title_full_unstemmed | Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex |
| title_short | Cryo-EM structure of the Mycobacterium smegmatis MmpL5-AcpM complex |
| title_sort | cryo em structure of the mycobacterium smegmatis mmpl5 acpm complex |
| topic | Mycobacterial membrane protein Large MmpL5 acyl carrier protein M mycobactin L siderophore export iron acquisition |
| url | https://journals.asm.org/doi/10.1128/mbio.03035-24 |
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