| Structural highlights
Function
[1433B_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2.[1] [2]
Publication Abstract from PubMed
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 14-3-3beta: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.
14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface.,Karlberg T, Hornyak P, Pinto AF, Milanova S, Ebrahimi M, Lindberg M, Pullen N, Nordstrom A, Loverli E, Caraballo R, Wong EV, Nareoja K, Thorsell AG, Elofsson M, De La Cruz EM, Bjorkegren C, Schuler H Nat Commun. 2018 Sep 17;9(1):3785. doi: 10.1038/s41467-018-06194-1. PMID:30224724[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu Y, Ross JF, Bodine PV, Billiard J. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol Endocrinol. 2007 Dec;21(12):3050-61. Epub 2007 Aug 23. PMID:17717073 doi:http://dx.doi.org/10.1210/me.2007-0323
- ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
- ↑ Karlberg T, Hornyak P, Pinto AF, Milanova S, Ebrahimi M, Lindberg M, Pullen N, Nordstrom A, Loverli E, Caraballo R, Wong EV, Nareoja K, Thorsell AG, Elofsson M, De La Cruz EM, Bjorkegren C, Schuler H. 14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface. Nat Commun. 2018 Sep 17;9(1):3785. doi: 10.1038/s41467-018-06194-1. PMID:30224724 doi:http://dx.doi.org/10.1038/s41467-018-06194-1
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