Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action
Two-component systems (TCS) are protein machineries that enable cells to respond to input signals. Histidine kinases (HK) are the sensory component, transferring information toward downstream response regulators (RR). HKs transfer phosphoryl groups to their specific RRs, but also dephosphorylate the...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/21422 |
| _version_ | 1811181512660353024 |
|---|---|
| author | Felipe Trajtenberg Juan A Imelio Matías R Machado Nicole Larrieux Marcelo A Marti Gonzalo Obal Ariel E Mechaly Alejandro Buschiazzo |
| author_facet | Felipe Trajtenberg Juan A Imelio Matías R Machado Nicole Larrieux Marcelo A Marti Gonzalo Obal Ariel E Mechaly Alejandro Buschiazzo |
| author_sort | Felipe Trajtenberg |
| collection | DOAJ |
| description | Two-component systems (TCS) are protein machineries that enable cells to respond to input signals. Histidine kinases (HK) are the sensory component, transferring information toward downstream response regulators (RR). HKs transfer phosphoryl groups to their specific RRs, but also dephosphorylate them, overall ensuring proper signaling. The mechanisms by which HKs discriminate between such disparate directions, are yet unknown. We now disclose crystal structures of the HK:RR complex DesK:DesR from Bacillus subtilis, comprising snapshots of the phosphotransfer and the dephosphorylation reactions. The HK dictates the reactional outcome through conformational rearrangements that include the reactive histidine. The phosphotransfer center is asymmetric, poised for dissociative nucleophilic substitution. The structural bases of HK phosphatase/phosphotransferase control are uncovered, and the unexpected discovery of a dissociative reactional center, sheds light on the evolution of TCS phosphotransfer reversibility. Our findings should be applicable to a broad range of signaling systems and instrumental in synthetic TCS rewiring. |
| first_indexed | 2024-04-11T09:17:28Z |
| format | Article |
| id | doaj.art-d2b0357f0c4f43a69ceb7240ab367c16 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:17:28Z |
| publishDate | 2016-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d2b0357f0c4f43a69ceb7240ab367c162022-12-22T04:32:17ZengeLife Sciences Publications LtdeLife2050-084X2016-12-01510.7554/eLife.21422Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in actionFelipe Trajtenberg0Juan A Imelio1Matías R Machado2Nicole Larrieux3Marcelo A Marti4Gonzalo Obal5Ariel E Mechaly6Alejandro Buschiazzo7https://orcid.org/0000-0002-2509-6526Laboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, UruguayLaboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, UruguayBiomolecular Simulations, Institut Pasteur de Montevideo, Montevideo, UruguayLaboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, UruguayDepartamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, ArgentinaProtein Biophysics Unit, Institut Pasteur de Montevideo, Montevideo, UruguayLaboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, UruguayLaboratory of Molecular and Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay; Département de Microbiologie, Institut Pasteur, Paris, FranceTwo-component systems (TCS) are protein machineries that enable cells to respond to input signals. Histidine kinases (HK) are the sensory component, transferring information toward downstream response regulators (RR). HKs transfer phosphoryl groups to their specific RRs, but also dephosphorylate them, overall ensuring proper signaling. The mechanisms by which HKs discriminate between such disparate directions, are yet unknown. We now disclose crystal structures of the HK:RR complex DesK:DesR from Bacillus subtilis, comprising snapshots of the phosphotransfer and the dephosphorylation reactions. The HK dictates the reactional outcome through conformational rearrangements that include the reactive histidine. The phosphotransfer center is asymmetric, poised for dissociative nucleophilic substitution. The structural bases of HK phosphatase/phosphotransferase control are uncovered, and the unexpected discovery of a dissociative reactional center, sheds light on the evolution of TCS phosphotransfer reversibility. Our findings should be applicable to a broad range of signaling systems and instrumental in synthetic TCS rewiring.https://elifesciences.org/articles/21422two component systemscell signalingstructural biologyallosteric control of protein functionphosphoryl-transfer mechanism |
| spellingShingle | Felipe Trajtenberg Juan A Imelio Matías R Machado Nicole Larrieux Marcelo A Marti Gonzalo Obal Ariel E Mechaly Alejandro Buschiazzo Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action eLife two component systems cell signaling structural biology allosteric control of protein function phosphoryl-transfer mechanism |
| title | Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action |
| title_full | Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action |
| title_fullStr | Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action |
| title_full_unstemmed | Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action |
| title_short | Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action |
| title_sort | regulation of signaling directionality revealed by 3d snapshots of a kinase regulator complex in action |
| topic | two component systems cell signaling structural biology allosteric control of protein function phosphoryl-transfer mechanism |
| url | https://elifesciences.org/articles/21422 |
| work_keys_str_mv | AT felipetrajtenberg regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT juanaimelio regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT matiasrmachado regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT nicolelarrieux regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT marceloamarti regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT gonzaloobal regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT arielemechaly regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction AT alejandrobuschiazzo regulationofsignalingdirectionalityrevealedby3dsnapshotsofakinaseregulatorcomplexinaction |