ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores

被引：22

作者：

Mabanglo, Mark F. ^{[1
]}

Leung, Elisa ^{[1
]}

Vahidi, Siavash ^{[1
,2
,3
,4
]}

Seraphim, Thiago, V ^{[1
,5
]}

Eger, Bryan T. ^{[1
]}

Bryson, Steve ^{[1
,6
]}

Bhandari, Vaibhav ^{[1
]}

Zhou, Jin Lin ^{[3
]}

Mao, Yu-Qian ^{[1
]}

Rizzolo, Kamran ^{[1
]}

Barghash, Marim M. ^{[1
]}

Goodreid, Jordan D. ^{[3
]}

Phanse, Sadhna ^{[1
,5
]}

Babu, Mohan ^{[5
]}

Barbosa, Leandro R. S. ^{[7
]}

Ramos, Carlos H., I ^{[8
]}

Batey, Robert A. ^{[3
]}

Kay, Lewis E. ^{[1
,2
,3
,4
]}

Pai, Emil F. ^{[1
,2
,6
,9
]}

Houry, Walid A. ^{[1
,3
]}

机构：

[1] Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada

[4] Hosp Sick Children, Program Mol Med, Res Inst, Toronto, ON M5G 0A4, Canada

[5] Univ Regina, Dept Biochem, Regina, SK S4S 0A2, Canada

[6] Princess Margaret Hosp, Campbell Family Inst Canc Res, Ontario Canc Inst, Toronto, ON M5G 1L7, Canada

[7] Univ Sao Paulo, Inst Phys, BR-05508090 Sao Paulo, SP, Brazil

[8] Univ Estadual Campinas, UNICAMP, Inst Chem, BR-13083970 Campinas, SP, Brazil

[9] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada

来源：

COMMUNICATIONS BIOLOGY | 2019年 / 2卷 / 1期

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院; 英国惠康基金; 加拿大创新基金会; 巴西圣保罗研究基金会;

关键词：

ACYLDEPSIPEPTIDE ANALOGS; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; BETA-LACTONES; INHIBITORS; MODEL; CIPP; INSIGHTS; IDENTIFICATION; RESOLUTION;

D O I：

10.1038/s42003-019-0656-3

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia co ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation.

引用

页数：14