CTP-dependent molecular switches: an emerging new principle in cellular regulation

Introduction

Nucleotide-dependent molecular switches play key roles in the regulation of cellular processes such as translation, protein folding and transport, cytoskeletal dynamics, and cell differentiation. Until recently, their function was thought to rely exclusively on the purine nucleotides GTP or ATP as cofactors. This paradigm changed in 2019, when my group identified a fundamentally new class of regulatory switches, now called C-switches, that depend on the pyrimidine nucleotide CTP.

Importance of C-Switches

The few C-switches studied to date have important functions in bacterial growth and pathogenicity. Database searches predict that C-switches are highly diverse and widespread in nature. However, the physiological roles and modes of action of these proteins are still largely enigmatic.

Goals of C-SWITCH

The overarching goal of C-SWITCH is to provide comprehensive insight into the biology of C-switches and clarify the ways in which this newly identified regulatory principle can control protein activity and cellular functions.

Methodology

For this purpose, we will employ both bioinformatic and experimental methods to:

1. Systematically identify new types of C-switch proteins.
2. Perform detailed mechanistic studies of prototypic representatives, using state-of-the-art in vitro and in vivo approaches.

Impact of C-SWITCH

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.

Pharmacological Potential

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.