SPP 1710:  Dynamics of Thiol-Based Redox Switches in Cellular Physiology

• Subject Area: Biology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237042534

In recent years it has become evident that reactive oxygen and nitrogen species, despite their traditional reputation as components of radical chains and harbingers of damage, act as physiologically essential messengers in signal transduction. The signalling properties of particular oxidants are primarily sensed and mediated by "protein thiol switches", which are protein thiols that are specifically and reversibly modified by oxidation, thereby switching the protein between different conformational and functional states. In spite of the fundamental cell biological and medical importance of thiol switches we are only beginning to understand their principles of specificity, their mechanism of action and their role in the spatio-temporal operation of signal transduction.
Based on this new perception and recent pioneering technical developments, an interdisciplinary consortium of more than 30 scientists joined forces within the Priority Programme to synergistically address the following fundamental questions in the field of redox signalling and thiol-based redox regulation:
(1) What are the molecular mechanisms underlying protein thiol switches, and how can we explain their specificity and efficiency?
(2) Which redox signalling events and thiol switch changes do occur in the living organism and what are the species-specific differences?
(3) What are the physiological roles of redox signals within the overall cellular signalling circuitry and decision-making?
In order to adequately address these questions, novel interdisciplinary concepts and approaches will be combined with stringent technological advancement. We plan to clarify the precise biochemistry of the events under study. We plan to obtain high-resolution structural, functional, quantitative and spatio-temporal information on in vivo redox events and their dynamics. And we plan to identify, monitor and specifically manipulate individual thiol switches in vivo.
Within the Priority Programme, expertise, chosen experimental approaches and technology is exchanged and made available in a highly synergistic way aiming to cross the borders between disciplines, between subcellular compartments, between thiol switch proteins of interest and between model organisms - ranging from bacteria, protozoa, yeast and plants to mammals. The Priority Programme comprises individual groups and projects approaching the joint interest in thiol switches from different angles.

• DFG Programme: Priority Programmes
• International Connection: Netherlands, USA

Projects

• A conserved and multifunctional redox switch in yeast Get3 and mammalian TRC40 (Applicant Schwappach-Pignataro, Blanche )
• A dual STIM2 redox switch in melanoma immunology (Applicants Bogeski, Ivan ;  Hoth, Markus )
• Analysis of dynamic interactions of ROXYs, land plant-specific glutaredoxins, with TGA transcription factors during the evolution of land plants (Applicants Gutsche, Nora ;  Zachgo, Sabine )
• Central role of the monothiol-glutaredoxin GrxS17 in shoot apex differentiation upon flowering induction (Applicant Scheibe, Renate )
• Coordination Funds (Applicant Dick, Tobias )
• Functional analysis of ROXY-type glutaredoxin ROXY19 in Arabidopsis thaliana (Applicant Gatz, Christiane )
• Functional characterization of cysteines in Lck and Zap-70 and identification of new targets of oxidation in lymphocytes under physiological and pathological conditions. (Applicant Simeoni, Luca )
• Functional characterization of NaOCl-sensitive thiol-switches and their impact on the BSH redox potential in Staphylococcus aureus (Applicant Antelmann, Haike )
• Functional evaluation of monomeric glutathione peroxidase 8 (Gpx8) as a mammalian redox sensor in the ER (Applicant Conrad, Marcus )
• Genetically encoded biosensors for monitoring redox changes in the trypanothione-based thiol metabolism of trypanosomes (Applicant Krauth-Siegel, R. Luise )
• Genetically encoded probes for the real-time observation of intracellular hydropersulfide generation (Applicant Dick, Tobias )
• H2O2-dependent redox homeostasis in a zebrafish model of endocrine disease (Applicant Dickmeis, Thomas )
• Identification and characterization of thiol switches controlling the yeast metabolic cycle (Applicant Morgan, Bruce )
• Initiation, propagation and molecular integration of physiological and pathological redox signals in neurons (Applicants Kerschensteiner, Martin ;  Misgeld, Thomas )
• Intra- and intercellular functions of redoxins during neuroinflammation (Applicants Berndt, Carsten ;  Hanschmann, Eva-Maria )
• Long-range electrostatic interactions contribute to the target specificity and reactivity of thioredoxin family proteins (Applicant Lillig, Christopher Horst )
• Protein-disulfide isomerase: the decisive off-switch of a disintegrin and metalloprotease-17 (Applicant Lorenzen, Inken )
• Quantitative and mechanistic assessment of thiol switches by stopped-flow kinetic measurements (Applicant Deponte, Marcel )
• Quantitative in vivo mapping and analysis of physiological H2O2 - dependent redox homeostasis in zebrafish (Applicant Strähle, Uwe )
• Redox-control of the active/deactive transition of mitochondrial complex I (Applicant Brandt, Ulrich )
• Redox regulation of human adenylate kinase 2 (AK2), an essential key controller of energy metabolism (Applicant Riemer, Jan )
• Redox-sensitive switches in the core S-assimilation/GSH-biosynthetic pathway of plants (Applicants Hell, Rüdiger ;  Rausch, Thomas ;  Wirtz, Ph.D., Markus )
• Role of redox-active thiols in the biogenesis of cytosolic and nuclear iron-sulfur proteins (Applicant Lill, Roland )
• Seed germination control through mitochondrial thiol switches (Applicant Schwarzländer, Markus )
• Targeting spectrin redox switches to regulate the mechanoproperties of red blood cells. (Applicants Cortese-Krott, Miriam Margherita ;  Gohlke, Holger )
• The glutathione redox couple as a thiol switch operator in the malaria parasite Plasmodium falciparum (Applicant Rahlfs, Stefan )
• The integration of the cyclophilin 20-3 and 2-cysteine peroxiredoxin thiol switches in the redox regulatory network of the chloroplast (Applicant Dietz, Karl-Josef )
• Thiol-based Redox Control of Tetrapyrrole Metabolism: Posttranslational Control of Tetrapyrrole Biosynthesis Enzymes by NADPH-Dependent Thioredoxin Reductase C (NTRC) and Thioredoxins (Applicant Grimm, Bernhard )
• Thiol-based regulation of oxidative protein folding in the ER of plants (Applicant Meyer, Andreas )
• Thiol-based regulation of protein modifications in a host-pathogen setting (Applicant Leichert, Lars )
• Thiol-based switches in integrins: molecular analysis and redox-regulatory implications in cell-matrix interaction and migration. (Applicant Eble, Johannes Andreas )
• Thiol-switch control in A/B toxin cell entry and compartmental trafficking (Applicant Schmitt, Manfred Josef )
• Thiol switches controlled by the glutathione-S-transferase GDAP1 (Applicants Methner, Axel ;  Tenzer, Stefan )
• Thiol Switches Controlling Mitochondrial Protein Biogenesis (Applicant Herrmann, Johannes M. )

• Spokespersons: Professorin Dr. Katja Becker, from 2/2014 until 12/2019; Professor Dr. Tobias Dick, since 1/2020