Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

Abstract

Cellular signaling systems transmit information over long distances using allosteric transitions and/or post-translational modifications. In two-component systems the sensor histidine kinase and response regulator are wired through phosphoryl-transfer reactions, using either a uni- or bi-directional transmission mode, allowing to build rich regulatory networks. Using the thermosensor DesK-DesR two-component system from Bacillus subtilis and combining crystal structures, QM/MM calculations and integrative kinetic modeling, we uncover that: i) longer or shorter distances between the phosphoryl-acceptor and -donor residues can shift the phosphoryl-transfer equilibrium; ii) the phosphorylation-dependent dimerization of the regulator acts as a sequestering mechanism by preventing the interaction with the histidine kinase; and iii) the kinase's intrinsic conformational equilibrium makes the phosphotransferase state unlikely in the absence of histidine phosphorylation, minimizing backwards transmission. These mechanisms allow the system to control the direction of signal transmission in a very efficient way, showcasing the key role that structure-encoded allostery plays in signaling proteins to store and transmit information.

Current landscape and future directions of synthetic biology in South America

“…Examples are found in the Faculty of Science where Gonzalo Moratorio explores the use of SynBio to study the experimental evolution of viruses (Moratorio 2020;Pintó et al, 2021), Vanessa Amarelle from IIBCE that of seeks new "regulatory parts" from metagenomic libraries in collaboration with Guazzaroni group at USP Ribeirao Preto (Westmann et al, 2018;Amarelle et al, 2019) and Raúl Platero that participate in the assembly of modular vectors with standard architecture during its postdoc in Victor's de Lorenzo group in Madrid (Silva- Rocha et al, 2013). A close inspection of funded projects by the Uruguayan Agency for Investigation and Innovation allows us to identify other groups strongly working in SynBio approaches, such as Felipe Trajtemberg groups 52 that exploit its experience in structural biology to design new sensing/response devices (Lima et al, 2021). Uruguay has seen a considerable investment of state resources in education (≈4.5% of the gross domestic product, GDP), as well as in research and development (≈0.5% of the GDP) 53 .…”