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Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective

1
Unité des Toxines Bactériennes, UMR CNRS 2001, Institut Pasteur, 75015 Paris, France
2
Université de Paris, Sorbonne Paris Cité, 75006 Paris, France
3
Unité de Bioinformatique Structurale, UMR CNRS 3528, Institut Pasteur, 75015 Paris, France
4
Centre de Bioinformatique, Biostatistique et Biologie Intégrative, USR CNRS 3756, Institut Pasteur, 75015 Paris, France
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(18), 10129; https://doi.org/10.3390/ijms221810129
Received: 9 August 2021 / Revised: 11 September 2021 / Accepted: 14 September 2021 / Published: 20 September 2021
(This article belongs to the Section Biochemistry)
The cytotoxic necrotizing factor 1 (CNF1) toxin from uropathogenic Escherichia coli constitutively activates Rho GTPases by catalyzing the deamidation of a critical glutamine residue located in the switch II (SWII). In crystallographic structures of the CNF1 catalytic domain (CNF1CD), surface-exposed P768 and P968 peptidyl-prolyl imide bonds (X-Pro) adopt an unusual cis conformation. Here, we show that mutation of each proline residue into glycine abrogates CNF1CD in vitro deamidase activity, while mutant forms of CNF1 remain functional on RhoA in cells. Using molecular dynamics simulations coupled to protein-peptide docking, we highlight the long-distance impact of peptidyl-prolyl cis-trans isomerization on the network of interactions between the loops bordering the entrance of the catalytic cleft. The energetically favorable isomerization of P768 compared with P968, induces an enlargement of loop L1 that fosters the invasion of CNF1CD catalytic cleft by a peptide encompassing SWII of RhoA. The connection of the P968 cis isomer to the catalytic cysteine C866 via a ladder of stacking interactions is alleviated along the cis-trans isomerization. Finally, the cis-trans conversion of P768 favors a switch of the thiol side chain of C866 from a resting to an active orientation. The long-distance impact of peptidyl-prolyl cis-trans isomerizations is expected to have implications for target modification. View Full-Text
Keywords: Escherichia coli; CNF1; deamidase; X-Pro imide bond; peptidyl prolyl cis-trans isomerization; molecular dynamics; peptide docking Escherichia coli; CNF1; deamidase; X-Pro imide bond; peptidyl prolyl cis-trans isomerization; molecular dynamics; peptide docking
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MDPI and ACS Style

Paillares, E.; Marechal, M.; Swistak, L.; Tsoumtsa Meda, L.; Lemichez, E.; Malliavin, T.E. Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective. Int. J. Mol. Sci. 2021, 22, 10129. https://doi.org/10.3390/ijms221810129

AMA Style

Paillares E, Marechal M, Swistak L, Tsoumtsa Meda L, Lemichez E, Malliavin TE. Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective. International Journal of Molecular Sciences. 2021; 22(18):10129. https://doi.org/10.3390/ijms221810129

Chicago/Turabian Style

Paillares, Eléa, Maud Marechal, Léa Swistak, Landry Tsoumtsa Meda, Emmanuel Lemichez, and Thérèse E. Malliavin 2021. "Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective" International Journal of Molecular Sciences 22, no. 18: 10129. https://doi.org/10.3390/ijms221810129

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