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A type VII-secreted lipase toxin with reverse domain arrangement

Author

Listed:
  • Stephen R. Garrett

    (Newcastle University)

  • Nicole Mietrach

    (Newcastle University)

  • Justin Deme

    (Center for Structural Biology, Center for Cancer Research, National Cancer Institute, NIH)

  • Alina Bitzer

    (University of Tübingen)

  • Yaping Yang

    (Newcastle University)

  • Fatima R. Ulhuq

    (Newcastle University)

  • Dorothee Kretschmer

    (University of Tübingen)

  • Simon Heilbronner

    (University of Tübingen
    partner site Tübingen)

  • Terry K. Smith

    (University of St. Andrews, North Haugh)

  • Susan M. Lea

    (Center for Structural Biology, Center for Cancer Research, National Cancer Institute, NIH)

  • Tracy Palmer

    (Newcastle University)

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.

Suggested Citation

  • 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, 2023. "A type VII-secreted lipase toxin with reverse domain arrangement," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44221-y
    DOI: 10.1038/s41467-023-44221-y
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    References listed on IDEAS

    as
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