14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface

Tobias Karlberg, Peter Hornyak, Ana Filipa Pinto, Stefina Milanova, Mahsa Ebrahimi, Mikael Lindberg, Nikolai Püllen, Axel Nordström, Elinor Löverli, Rémi Caraballo, Emily V. Wong, Katja Näreoja, Ann-Gerd Thorsell, Mikael Elofsson, Enrique M. Cruz, Camilla Björkegren and Herwig Schüler ()
Additional contact information
Tobias Karlberg: Karolinska Institutet
Peter Hornyak: Karolinska Institutet
Ana Filipa Pinto: Karolinska Institutet
Stefina Milanova: Karolinska Institutet
Mahsa Ebrahimi: Karolinska Institutet
Mikael Lindberg: Umeå University
Nikolai Püllen: Karolinska Institutet
Axel Nordström: Karolinska Institutet
Elinor Löverli: Karolinska Institutet
Rémi Caraballo: Umeå University
Emily V. Wong: Yale University
Katja Näreoja: Karolinska Institutet
Ann-Gerd Thorsell: Karolinska Institutet
Mikael Elofsson: Umeå University
Enrique M. Cruz: Yale University
Camilla Björkegren: Karolinska Institutet
Herwig Schüler: Karolinska Institutet

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3β:ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.

Date: 2018
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DOI: 10.1038/s41467-018-06194-1

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