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Intercepting second-messenger signaling by rationally designed peptides sequestering c-di-GMP

Hee, Chee-Seng and Habazettl, Judith and Schmutz, Christoph and Schirmer, Tilman and Jenal, Urs and Grzesiek, Stephan. (2020) Intercepting second-messenger signaling by rationally designed peptides sequestering c-di-GMP. Proceedings of the National Academy of Sciences of the United States of America, 117 (29). pp. 17211-17220.

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Abstract

The bacterial second messenger cyclic diguanylate (c-di-GMP) regulates a wide range of cellular functions from biofilm formation to growth and survival. Targeting a second-messenger network is challenging because the system involves a multitude of components with often overlapping functions. Here, we present a strategy to intercept c-di-GMP signaling pathways by directly targeting the second messenger. For this, we developed a c-di-GMP-sequestering peptide (CSP) that was derived from a CheY-like c-di-GMP effector protein. CSP binds c-di-GMP with submicromolar affinity. The elucidation of the CSP⋅c-di-GMP complex structure by NMR identified a linear c-di-GMP-binding motif, in which a self-intercalated c-di-GMP dimer is tightly bound by a network of H bonds and π-stacking interactions involving arginine and aromatic residues. Structure-based mutagenesis yielded a variant with considerably higher, low-nanomolar affinity, which subsequently was shortened to 19 residues with almost uncompromised affinity. We demonstrate that endogenously expressed CSP intercepts c-di-GMP signaling and effectively inhibits biofilm formation in Pseudomonas aeruginosa , the most widely used model for serious biofilm-associated medical implications.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Jenal)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Molecular Microbiology (Jenal)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Schirmer)
UniBasel Contributors:Schirmer, Tilman and Hee, Chee Seng and Habazettl, Judith Maria and Schmutz, Christoph and Jenal, Urs and Grzesiek, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher: National Academy of Sciences
ISSN:0027-8424
e-ISSN:1091-6490
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:24 Nov 2020 10:26
Deposited On:24 Nov 2020 10:26

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