A type VII-secreted lipase toxin with reverse domain arrangement

Stephen R. Garrett, Nicole Mietrach, Justin Deme, Alina Bitzer, Yaping Yang, Fatima R. Ulhuq, Dorothee Kretschmer, Simon Heilbronner, Terry K. Smith, Susan M. Lea and Tracy Palmer ()
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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
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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44221-y

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