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

被引:36
作者
Karlberg, Tobias [1 ]
Hornyak, Peter [1 ]
Pinto, Ana Filipa [1 ]
Milanova, Stefina [2 ]
Ebrahimi, Mahsa [1 ]
Lindberg, Mikael [3 ]
Pullen, Nikolai [1 ]
Nordstrom, Axel [1 ]
Loverli, Elinor [1 ]
Caraballo, Remi [4 ]
Wong, Emily V. [5 ,6 ]
Nareoja, Katja [1 ]
Thorsell, Ann-Gerd [1 ]
Elofsson, Mikael [4 ]
De la Cruz, Enrique M. [5 ]
Bjorkegren, Camilla [1 ,2 ]
Schuler, Herwig [1 ]
机构
[1] Karolinska Inst, Dept Biosci & Nutr, Halsovagen 4c, S-14157 Huddinge, Sweden
[2] Karolinska Inst, Dept Cellular & Mol Biol, Berzelius Vag 35, S-17165 Solna, Sweden
[3] Umea Univ, Prot Expertise Platform, S-90187 Umea, Sweden
[4] Umea Univ, Dept Chem, S-90187 Umea, Sweden
[5] Yale Univ, Mol Biophys & Biochem, New Haven, CT 06520 USA
[6] Univ Calif San Francisco, Med Sch, Dept Biochem & Biophys, San Francisco, CA 94158 USA
基金
美国国家卫生研究院; 美国国家科学基金会; 瑞典研究理事会;
关键词
EXOENZYME-S; ADP-RIBOSYLTRANSFERASE; STRUCTURAL BASIS; AERUGINOSA; BINDING; IDENTIFICATION; RIBOSYLATION; EXPRESSION; INHIBITORS; PEPTIDES;
D O I
10.1038/s41467-018-06194-1
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 14-3-3 beta: 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.
引用
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页数:11
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