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

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

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

页数：11