1. Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action
- Author
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Marcelo A. Martí, Ariel E. Mechaly, Gonzalo Obal, J.A. Imelio, Nicole Larrieux, Alejandro Buschiazzo, Felipe Trajtenberg, Matías R. Machado, Molecular and structural microbiology / Microbiología Molecular y Estructural [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Biomolecular Simulations / Simulaciones Biomoleculares [Montevideo], Universidad de Buenos Aires [Buenos Aires] (UBA), Protein Biophysics [Montevideo] (UBP), Integrative Microbiology of Zoonotic Agents [Paris and Montevideo] (IMiZA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris], Agencia Nacional de Investigación e Innovación (FCE2009_1_2679)Agence Nationale de la Recherche (PCV06_138918)FOCEM (MERCOSUR Structural Convergence Fund) (COF 03/11)Centro de Biologia Estructural del MercosurAgencia Nacional de Investigación e Innovación (FCE2007_219), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris] (IP)
- Subjects
0301 basic medicine ,Models, Molecular ,MESH: Signal Transduction ,Histidine Kinase ,Protein Conformation ,Regulator ,Crystallography, X-Ray ,Phosphotransferase ,MESH: Protein Conformation ,biophysics ,B. subtilis ,Transferase ,structural biology ,Phosphorylation ,Biology (General) ,Microbiology and Infectious Disease ,Kinase ,General Neuroscience ,General Medicine ,MESH: Transcription Factors ,Biophysics and Structural Biology ,Cell biology ,Biochemistry ,MESH: Histidine Kinase ,Medicine ,phosphoryl-transfer mechanism ,MESH: Models, Molecular ,Research Article ,Bacillus subtilis ,Signal Transduction ,Cell signaling ,QH301-705.5 ,infectious disease ,Science ,Phosphatase ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Dephosphorylation ,03 medical and health sciences ,[CHIM.CRIS]Chemical Sciences/Cristallography ,cell signaling ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,030102 biochemistry & molecular biology ,General Immunology and Microbiology ,MESH: Phosphorylation ,microbiology ,E. coli ,MESH: Bacillus subtilis ,MESH: Crystallography, X-Ray ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,030104 developmental biology ,Structural biology ,MESH: Protein Processing, Post-Translational ,two component systems ,Protein Processing, Post-Translational ,Transcription Factors ,allosteric control of protein function - Abstract
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. DOI: http://dx.doi.org/10.7554/eLife.21422.001
- Published
- 2016