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, 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.
Citation
Garrett , S R , Mietrach , N , Deme , J , Bitzer , A , Yang , Y , Ulhuq , F R , Kretschmer , D , Heilbronner , S , Smith , T K , Lea , S M & Palmer , T 2023 , ' A type VII-secreted lipase toxin with reverse domain arrangement ' , Nature Communications , vol. 14 , 8438 . https://doi.org/10.1038/s41467-023-44221-y
Publication
Nature Communications
Status
Peer reviewed
ISSN
2041-1723Type
Journal article
Description
Funding: This study was supported by the Wellcome Trust (through Investigator Awards 10183/Z/15/Z and 224151/Z/21/Z to TP), the Intramural Research Program of the NIH, NCI, Center for Cancer Research (awarded to SML), the German Centre of Infection Research (DZIF) to SH (TTU 08.708). NM holds a Walter Benjamin Fellowship (M2871/1-1), funded by the DFG (German Research Foundation). Additionally, we acknowledge infrastructural funding by the DFG in the frame of Germany's Excellence Strategy—EXC 2124—390838134 (SH). SG is funded by the Newcastle-Liverpool-Durham BBSRC DTP2 Training Grant, project reference number BB/M011186/1 and YY by the China Scholarship Council.Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.