A type VII-secreted lipase toxin with reverse domain arrangement
Abstract The type VII protein secretion system (T7SS) is found in many Gram-positive bacteria and in pathogenic mycobacteria. All T7SS substrate proteins described to date share a common helical domain architecture at the N-terminus that typically interacts with other helical partner proteins, formi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44221-y |
| _version_ | 1797376907431378944 |
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| author | Stephen R. Garrett Nicole Mietrach Justin Deme Alina Bitzer Yaping Yang Fatima R. Ulhuq Dorothee Kretschmer Simon Heilbronner Terry K. Smith Susan M. Lea Tracy Palmer |
| author_facet | Stephen R. Garrett Nicole Mietrach Justin Deme Alina Bitzer Yaping Yang Fatima R. Ulhuq Dorothee Kretschmer Simon Heilbronner Terry K. Smith Susan M. Lea Tracy Palmer |
| author_sort | Stephen R. Garrett |
| collection | DOAJ |
| description | Abstract The type VII protein secretion system (T7SS) is found in many Gram-positive bacteria and in pathogenic mycobacteria. All T7SS substrate proteins described to date share a common helical domain architecture at the N-terminus that typically interacts with other helical partner proteins, forming a composite signal sequence for targeting to the T7SS. The C-terminal domains are functionally diverse and in Gram-positive bacteria such as Staphylococcus aureus often specify toxic anti-bacterial activity. Here we describe the first example of a class of T7 substrate, TslA, that has a reverse domain organisation. TslA is widely found across Bacillota including Staphylococcus, Enterococcus and Listeria. We show that the S. aureus TslA N-terminal domain is a phospholipase A with anti-staphylococcal activity that is neutralised by the immunity lipoprotein TilA. Two small helical partner proteins, TlaA1 and TlaA2 are essential for T7-dependent secretion of TslA and at least one of these interacts with the TslA C-terminal domain to form a helical stack. Cryo-EM analysis of purified TslA complexes indicate that they share structural similarity with canonical T7 substrates. Our findings suggest that the T7SS has the capacity to recognise a secretion signal present at either end of a substrate. |
| first_indexed | 2024-03-08T19:45:20Z |
| format | Article |
| id | doaj.art-614445c295ff47b0b6acfe1519669f17 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T19:45:20Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-614445c295ff47b0b6acfe1519669f172023-12-24T12:23:40ZengNature PortfolioNature Communications2041-17232023-12-0114111610.1038/s41467-023-44221-yA type VII-secreted lipase toxin with reverse domain arrangementStephen R. Garrett0Nicole Mietrach1Justin Deme2Alina Bitzer3Yaping Yang4Fatima R. Ulhuq5Dorothee Kretschmer6Simon Heilbronner7Terry K. Smith8Susan M. Lea9Tracy Palmer10Newcastle University Biosciences Institute, Newcastle UniversityNewcastle University Biosciences Institute, Newcastle UniversityCenter for Structural Biology, Center for Cancer Research, National Cancer Institute, NIHInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenNewcastle University Biosciences Institute, Newcastle UniversityNewcastle University Biosciences Institute, Newcastle UniversityInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenSchool of Biology, Biomedical Sciences Research Complex, University of St. Andrews, North HaughCenter for Structural Biology, Center for Cancer Research, National Cancer Institute, NIHNewcastle University Biosciences Institute, Newcastle UniversityAbstract The type VII protein secretion system (T7SS) is found in many Gram-positive bacteria and in pathogenic mycobacteria. All T7SS substrate proteins described to date share a common helical domain architecture at the N-terminus that typically interacts with other helical partner proteins, forming a composite signal sequence for targeting to the T7SS. The C-terminal domains are functionally diverse and in Gram-positive bacteria such as Staphylococcus aureus often specify toxic anti-bacterial activity. Here we describe the first example of a class of T7 substrate, TslA, that has a reverse domain organisation. TslA is widely found across Bacillota including Staphylococcus, Enterococcus and Listeria. We show that the S. aureus TslA N-terminal domain is a phospholipase A with anti-staphylococcal activity that is neutralised by the immunity lipoprotein TilA. Two small helical partner proteins, TlaA1 and TlaA2 are essential for T7-dependent secretion of TslA and at least one of these interacts with the TslA C-terminal domain to form a helical stack. Cryo-EM analysis of purified TslA complexes indicate that they share structural similarity with canonical T7 substrates. Our findings suggest that the T7SS has the capacity to recognise a secretion signal present at either end of a substrate.https://doi.org/10.1038/s41467-023-44221-y |
| spellingShingle | Stephen R. Garrett Nicole Mietrach Justin Deme Alina Bitzer Yaping Yang Fatima R. Ulhuq Dorothee Kretschmer Simon Heilbronner Terry K. Smith Susan M. Lea Tracy Palmer A type VII-secreted lipase toxin with reverse domain arrangement Nature Communications |
| title | A type VII-secreted lipase toxin with reverse domain arrangement |
| title_full | A type VII-secreted lipase toxin with reverse domain arrangement |
| title_fullStr | A type VII-secreted lipase toxin with reverse domain arrangement |
| title_full_unstemmed | A type VII-secreted lipase toxin with reverse domain arrangement |
| title_short | A type VII-secreted lipase toxin with reverse domain arrangement |
| title_sort | type vii secreted lipase toxin with reverse domain arrangement |
| url | https://doi.org/10.1038/s41467-023-44221-y |
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