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dc.contributor.author Abriata, Luciano Andres
dc.contributor.author Albanesi, Daniela
dc.contributor.author Dal Peraro, Matteo
dc.contributor.author de Mendoza, Diego
dc.date.available 2018-06-28T14:43:18Z
dc.date.issued 2017-06
dc.identifier.citation Abriata, Luciano Andres; Albanesi, Daniela; Dal Peraro, Matteo; de Mendoza, Diego; Signal Sensing and Transduction by Histidine Kinases as Unveiled through Studies on a Temperature Sensor; American Chemical Society; Accounts of Chemical Research; 50; 6; 6-2017; 1359-1366
dc.identifier.issn 0001-4842
dc.identifier.uri http://hdl.handle.net/11336/50337
dc.description.abstract Histidine kinases (HK) are the sensory proteins of two-component systems, responsible for a large fraction of bacterial responses to stimuli and environmental changes. Prototypical HKs are membrane-bound proteins that phosphorylate cognate response regulator proteins in the cytoplasm upon signal detection in the membrane or periplasm. HKs stand as potential drug targets but also constitute fascinating systems for studying proteins at work, specifically regarding the chemistry and mechanics of signal detection, transduction through the membrane, and regulation of catalytic outputs. In this Account, we focus on Bacillus subtilis DesK, a membrane-bound HK part of a two-component system that maintains appropriate membrane fluidity at low growth temperatures. Unlike most HKs, DesK has no extracytoplasmic signal-sensing domains; instead, sensing is carried out by 10 transmembrane helices (coming from two protomers) arranged in an unknown structure. The fifth transmembrane helix from each protomer connects, without any of the intermediate domains found in other HKs, into the dimerization and histidine phosphotransfer (DHp) domain located in the cytoplasm, which is followed by the ATP-binding domains (ABD). Throughout the years, genetic, biochemical, structural, and computational studies on wild-type, mutant, and truncated versions of DesK allowed us to dissect several aspects of DesK’s functioning, pushing forward a more general understanding of its own structure/function relationships as well as those of other HKs. We have shown that the sensing mechanism is rooted in temperature-dependent membrane properties, most likely a combination of thickness, fluidity, and water permeability, and we have proposed possible mechanisms by which DesK senses these properties and transduces the signals. X-ray structures and computational models have revealed structural features of TM and cytoplasmic regions in DesK’s kinase- and phosphatase-competent states. Biochemical and genetic experiments and molecular simulations further showed that reversible formation of a two-helix coiled coil in the fifth TM segment and the N-terminus of the cytoplasmic domain is essential for the sensing and signal transduction mechanisms. Together with other structural and functional works, the emerging picture suggests that diverse HKs possess distinct sensing and transduction mechanisms but share as rather general features (i) a symmetric phosphatase state and an asymmetric kinase state and (ii) similar functional outputs on the conserved DHp and ABD domains, achieved through different mechanisms that depend on the nature of the initial signal. We here advance (iii) an important role for TM prolines in transducing the initial signals to the cytoplasmic coiled coils, based on simulations of DesK’s TM helices and our previous work on a related HK, PhoQ. Lastly, evidence for DesK, PhoQ, BvgS, and DctB HKs shows that (iv) overall catalytic output is tuned by a delicate balance between hydration potentials, coiled coil stability, and exposure of hydrophobic surface patches at their cytoplasmic coiled coils and at the N-terminal and C-terminal sides of their TM helices. This balance is so delicate that small perturbations, either physiological signals or induced by mutations, lead to large remodeling of the underlying conformational landscape achieving clear-cut changes in catalytic output, mirroring the required response speed of these systems for proper biological function.
dc.format application/pdf
dc.language.iso eng
dc.publisher American Chemical Society
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject HISTIDINE KINASE
dc.subject SIGNAL SENSING
dc.subject SIGNAL TRANSDUCTION
dc.subject DESK
dc.subject BACILLUS SUBTILIS
dc.subject.classification Otras Ciencias Biológicas
dc.subject.classification Ciencias Biológicas
dc.subject.classification CIENCIAS NATURALES Y EXACTAS
dc.title Signal Sensing and Transduction by Histidine Kinases as Unveiled through Studies on a Temperature Sensor
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2018-06-28T14:04:25Z
dc.journal.volume 50
dc.journal.number 6
dc.journal.pagination 1359-1366
dc.journal.pais Estados Unidos
dc.journal.ciudad Maryland
dc.description.fil Fil: Abriata, Luciano Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Ecole Polytechnique Federale de Lausanne; Suiza. Swiss Institute of Bioinformatics; Suiza
dc.description.fil Fil: Albanesi, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil Fil: Dal Peraro, Matteo. Ecole Polytechnique Federale de Lausanne; Suiza. Swiss Institute of Bioinformatics; Suiza
dc.description.fil Fil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.journal.title Accounts of Chemical Research
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/acs.accounts.6b00593
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acs.accounts.6b00593
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)