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

DOI: 10.1038/s41467-018-06194-1 DOI Help

Authors: 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. De La Cruz (Yale University) , Camilla Björkegren (Karolinska Institutet) , Herwig Schüler (Karolinska Institutet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 11265 , 15806

Open Access Open Access

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.

Journal Keywords: exotoxin, chaperonin, 14-3-3 proteins, pseudomonas

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF and BESSY

Documents:
s41467-018-06194-1.pdf