Molecular switches play key roles in regulating essential cellular processes, including protein biosynthesis, cell growth, cytoskeletal dynamics, and cell differentiation. They are mediated by proteins that toggle between distinct conformational states – like electronic switches – to activate or deactivate processes precisely when and where needed within the cell. Switching depends on the binding and hydrolysis of nucleotides, which stabilize specific states until the next transition occurs. Transitionally, molecular switches were thought to rely exclusively on the structurally similar purine nucleotides GTP and ATP. However, this view shifted with the discovery of C-switches, a novel class of regulatory proteins whose function depends on the pyrimidine nucleotide CTP. Database searches suggest that C-switches may be highly diverse and widespread in nature. However, the physiological roles and modes of action of these proteins are still largely enigmatic.
The overarching goal of C-SWITCH is to provide comprehensive insight into the biology of C-switches and to clarify the ways in which this newly identified regulatory principle can control protein activity and cellular functions. For this purpose, the project will employ both bioinformatic and experimental methods to systematically identify new types of C-switch proteins and perform detailed mechanistic studies of prototypical representatives, using state-of-the-art in vitro and in vivo approaches. C-SWITCH will thus break new ground in the understanding of cellular regulation and pave the way to a global understanding of C-switches as versatile regulators in biology. Importantly, proteins containing a canonical C-switch domain are absent from humans and other mammalian systems. C-SWITCH will therefore also explore the pharmacological potential of C-switches as new targets for antibacterial and antivirulence therapies, thereby possibly opening new avenues for translational applications and supporting the current global effort to combat bacterial antibiotic resistance.
