Structural insights into substrate recognition by the type VII secretion system
Abstract Type VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1 [early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1~5) of T7SSs in Mtb, where it delivers virulence factors into host macro...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2019-11-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1007/s13238-019-00671-z |
| _version_ | 1827841268782202880 |
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| author | Shuhui Wang Kaixuan Zhou Xiaolin Yang Bing Zhang Yao Zhao Yu Xiao Xiuna Yang Haitao Yang Luke W. Guddat Jun Li Zihe Rao |
| author_facet | Shuhui Wang Kaixuan Zhou Xiaolin Yang Bing Zhang Yao Zhao Yu Xiao Xiuna Yang Haitao Yang Luke W. Guddat Jun Li Zihe Rao |
| author_sort | Shuhui Wang |
| collection | DOAJ |
| description | Abstract Type VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1 [early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1~5) of T7SSs in Mtb, where it delivers virulence factors into host macrophages during infection. However, little is known about the molecular details as to how this occurs. Here, we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS subtypes. These structures adopt a classic RecA-like ɑ/β fold with a conserved Mg-ATP binding site. The structure of EccCb1 in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module “LxxxMxF” for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop. A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family, suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs. A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation channel. The diameter of the channel is ~25-Å, with a size that would allow helix-bundle shaped substrate proteins to bind and pass through. Thus, our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion. |
| first_indexed | 2024-03-12T07:49:09Z |
| format | Article |
| id | doaj.art-923f424a78aa4ccd8baade42e800ce1a |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T07:49:09Z |
| publishDate | 2019-11-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-923f424a78aa4ccd8baade42e800ce1a2023-09-02T20:45:50ZengOxford University PressProtein & Cell1674-800X1674-80182019-11-0111212413710.1007/s13238-019-00671-zStructural insights into substrate recognition by the type VII secretion systemShuhui Wang0Kaixuan Zhou1Xiaolin Yang2Bing Zhang3Yao Zhao4Yu Xiao5Xiuna Yang6Haitao Yang7Luke W. Guddat8Jun Li9Zihe Rao10Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversitySchool of Chemistry and Molecular Biosciences, The University of QueenslandShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityAbstract Type VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1 [early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1~5) of T7SSs in Mtb, where it delivers virulence factors into host macrophages during infection. However, little is known about the molecular details as to how this occurs. Here, we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS subtypes. These structures adopt a classic RecA-like ɑ/β fold with a conserved Mg-ATP binding site. The structure of EccCb1 in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module “LxxxMxF” for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop. A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family, suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs. A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation channel. The diameter of the channel is ~25-Å, with a size that would allow helix-bundle shaped substrate proteins to bind and pass through. Thus, our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.http://link.springer.com/article/10.1007/s13238-019-00671-ztype VII secretion systemMycobacterium tuberculosisATPasevirulence factorsubstrate recognition |
| spellingShingle | Shuhui Wang Kaixuan Zhou Xiaolin Yang Bing Zhang Yao Zhao Yu Xiao Xiuna Yang Haitao Yang Luke W. Guddat Jun Li Zihe Rao Structural insights into substrate recognition by the type VII secretion system Protein & Cell type VII secretion system Mycobacterium tuberculosis ATPase virulence factor substrate recognition |
| title | Structural insights into substrate recognition by the type VII secretion system |
| title_full | Structural insights into substrate recognition by the type VII secretion system |
| title_fullStr | Structural insights into substrate recognition by the type VII secretion system |
| title_full_unstemmed | Structural insights into substrate recognition by the type VII secretion system |
| title_short | Structural insights into substrate recognition by the type VII secretion system |
| title_sort | structural insights into substrate recognition by the type vii secretion system |
| topic | type VII secretion system Mycobacterium tuberculosis ATPase virulence factor substrate recognition |
| url | http://link.springer.com/article/10.1007/s13238-019-00671-z |
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