Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion
The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2014-12-01
|
| Series: | Toxins |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2072-6651/7/1/1 |
| _version_ | 1811298344801140736 |
|---|---|
| author | Ana-Cristina Sotomayor-Pérez Daniel Ladant Alexandre Chenal |
| author_facet | Ana-Cristina Sotomayor-Pérez Daniel Ladant Alexandre Chenal |
| author_sort | Ana-Cristina Sotomayor-Pérez |
| collection | DOAJ |
| description | The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria. We have investigated several RTX-containing polypeptides of different lengths, all derived from the Bordetella pertussis adenylate cyclase toxin, CyaA. Using a combination of experimental approaches, we showed that the RTX proteins exhibit the hallmarks of intrinsically disordered proteins in the absence of calcium. This intrinsic disorder mainly results from internal electrostatic repulsions between negatively charged residues of the RTX motifs. Calcium binding triggers a strong reduction of the mean net charge, dehydration and compaction, folding and stabilization of secondary and tertiary structures of the RTX proteins. We propose that the intrinsically disordered character of the RTX proteins may facilitate the uptake and secretion of virulence factors through the bacterial secretion machinery. These results support the hypothesis that the folding reaction is achieved upon protein secretion and, in the case of proteins containing RTX motifs, could be finely regulated by the calcium gradient across bacterial cell wall. |
| first_indexed | 2024-04-13T06:18:06Z |
| format | Article |
| id | doaj.art-75087bad33d64ae1adcdc06cb65ad969 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-04-13T06:18:06Z |
| publishDate | 2014-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-75087bad33d64ae1adcdc06cb65ad9692022-12-22T02:58:44ZengMDPI AGToxins2072-66512014-12-017112010.3390/toxins7010001toxins7010001Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin SecretionAna-Cristina Sotomayor-Pérez0Daniel Ladant1Alexandre Chenal2Institut Pasteur, CNRS UMR 3528, Unité de Biochimie des Interactions Macromoléculaires, Département de Biologie Structurale et Chimie, 28 rue du Dr Roux, Paris cedex 15 75724, FranceInstitut Pasteur, CNRS UMR 3528, Unité de Biochimie des Interactions Macromoléculaires, Département de Biologie Structurale et Chimie, 28 rue du Dr Roux, Paris cedex 15 75724, FranceInstitut Pasteur, CNRS UMR 3528, Unité de Biochimie des Interactions Macromoléculaires, Département de Biologie Structurale et Chimie, 28 rue du Dr Roux, Paris cedex 15 75724, FranceThe past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria. We have investigated several RTX-containing polypeptides of different lengths, all derived from the Bordetella pertussis adenylate cyclase toxin, CyaA. Using a combination of experimental approaches, we showed that the RTX proteins exhibit the hallmarks of intrinsically disordered proteins in the absence of calcium. This intrinsic disorder mainly results from internal electrostatic repulsions between negatively charged residues of the RTX motifs. Calcium binding triggers a strong reduction of the mean net charge, dehydration and compaction, folding and stabilization of secondary and tertiary structures of the RTX proteins. We propose that the intrinsically disordered character of the RTX proteins may facilitate the uptake and secretion of virulence factors through the bacterial secretion machinery. These results support the hypothesis that the folding reaction is achieved upon protein secretion and, in the case of proteins containing RTX motifs, could be finely regulated by the calcium gradient across bacterial cell wall.http://www.mdpi.com/2072-6651/7/1/1adenylate cyclase CyaA toxinintrinsically disordered proteins (IDP)natively unfolded proteinsrepeat in toxin (RTX)calcium-binding proteinscalcium-induced protein folding |
| spellingShingle | Ana-Cristina Sotomayor-Pérez Daniel Ladant Alexandre Chenal Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion Toxins adenylate cyclase CyaA toxin intrinsically disordered proteins (IDP) natively unfolded proteins repeat in toxin (RTX) calcium-binding proteins calcium-induced protein folding |
| title | Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion |
| title_full | Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion |
| title_fullStr | Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion |
| title_full_unstemmed | Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion |
| title_short | Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion |
| title_sort | disorder to order transition in the cyaa toxin rtx domain implications for toxin secretion |
| topic | adenylate cyclase CyaA toxin intrinsically disordered proteins (IDP) natively unfolded proteins repeat in toxin (RTX) calcium-binding proteins calcium-induced protein folding |
| url | http://www.mdpi.com/2072-6651/7/1/1 |
| work_keys_str_mv | AT anacristinasotomayorperez disordertoordertransitioninthecyaatoxinrtxdomainimplicationsfortoxinsecretion AT danielladant disordertoordertransitioninthecyaatoxinrtxdomainimplicationsfortoxinsecretion AT alexandrechenal disordertoordertransitioninthecyaatoxinrtxdomainimplicationsfortoxinsecretion |