Structure of a tripartite protein complex that targets toxins to the type VII secretion system

Type VII secretion systems are membrane-embedded nanomachines used by Gram-positive bacteria to export effector proteins from the cytoplasm to the extracellular environment. Many of these effectors are polymorphic toxins comprised of an N-terminal Leu-x-Gly (LXG) domain of unknown function and a C-t...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 3; p. e2312455121
Main Authors:	Klein, Timothy A, Shah, Prakhar Y, Gkragkopoulou, Polyniki, Grebenc, Dirk W, Kim, Youngchang, Whitney, John C
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 16-01-2024
Subjects:	Animals Bacteria BASIC BIOLOGICAL SCIENCES Biological Sciences Cytoplasm Effectors Elongated structure Gram-positive bacteria Grasshoppers Hydrophobicity LAP protein Opportunist infection Protein structure Proteins Science & Technology - Other Topics Secretion Toxins Toxins, Biological Type VII Secretion Systems - genetics structural biology protein biochemistry protein export bacterial toxins bacterial secretion systems
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Summary:	Type VII secretion systems are membrane-embedded nanomachines used by Gram-positive bacteria to export effector proteins from the cytoplasm to the extracellular environment. Many of these effectors are polymorphic toxins comprised of an N-terminal Leu-x-Gly (LXG) domain of unknown function and a C-terminal toxin domain that inhibits the growth of bacterial competitors. In recent work, it was shown that LXG effectors require two cognate Lap proteins for T7SS-dependent export. Here, we present the 2.6 Å structure of the LXG domain of the TelA toxin from the opportunistic pathogen in complex with both of its cognate Lap targeting factors. The structure reveals an elongated α-helical bundle within which each Lap protein makes extensive hydrophobic contacts with either end of the LXG domain. Remarkably, despite low overall sequence identity, we identify striking structural similarity between our LXG complex and PE-PPE heterodimers exported by the distantly related ESX type VII secretion systems of Mycobacteria implying a conserved mechanism of effector export among diverse Gram-positive bacteria. Overall, our findings demonstrate that LXG domains, in conjunction with their cognate Lap targeting factors, represent a tripartite secretion signal for a widespread family of T7SS toxins.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-06CH11357 USDOE Edited by Roy Curtiss III, University of Florida, Gainesville, FL; received July 20, 2023; accepted November 20, 2023 1T.A.K. and P.Y.S. contributed equally to this work.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.2312455121