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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Mabanglo, Mark F. [1] ; Leung, Elisa [1] ; Vahidi, Siavash [2, 3, 4, 1] ; Seraphim, V, Thiago ; Eger, Bryan T. [5] ; Bryson, Steve [5, 6] ; Bhandari, Vaibhav [5] ; Zhou, Jin Lin [2] ; Mao, Yu-Qian [5] ; Rizzolo, Kamran [5] ; Barghash, Marim M. [5] ; Goodreid, Jordan D. [2] ; Phanse, Sadhna [5, 7] ; Babu, Mohan [7] ; Barbosa, Leandro R. S. [8] ; Ramos, I, Carlos H. ; Batey, Robert A. [2] ; Kay, Lewis E. [2, 3, 5, 4] ; Pai, Emil F. [3, 5, 6, 9] ; Houry, Walid A. [2, 5]
Total Authors: 20
[1] Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[2] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6 - Canada
[3] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8 - Canada
[4] Hosp Sick Children, Program Mol Med, Res Inst, Toronto, ON M5G 0A4 - Canada
[5] Seraphim, Thiago, V, Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[6] Princess Margaret Hosp, Campbell Family Inst Canc Res, Ontario Canc Inst, Toronto, ON M5G 1L7 - Canada
[7] Seraphim, Thiago, V, Univ Regina, Dept Biochem, Regina, SK S4S 0A2 - Canada
[8] Univ Sao Paulo, Inst Phys, BR-05508090 Sao Paulo, SP - Brazil
[9] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8 - Canada
Total Affiliations: 9
Document type: Journal article
Source: COMMUNICATIONS BIOLOGY; v. 2, NOV 13 2019.
Web of Science Citations: 0

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. (AU)

FAPESP's process: 16/05019-0 - The thermodynamical and structural influence of ionic liquids in biomimetic membrane models
Grantee:Natália Fernandes de Oliveira
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 15/15822-1 - Physicochemical and structural properties of Ionic Liquids and drugs interacting with biologicaly relevant systems.
Grantee:Leandro Ramos Souza Barbosa
Support type: Regular Research Grants
FAPESP's process: 12/50161-8 - Study of the structure and function of the Hsp90 chaperone with emphasis on its role in cellular homeostasis
Grantee:Carlos Henrique Inacio Ramos
Support type: Research Projects - Thematic Grants
FAPESP's process: 12/01953-9 - Proteins under fibrillation process: a structural and spectroscopic study of the influence of denaturating agents
Grantee:Leandro Ramos Souza Barbosa
Support type: Regular Research Grants