Substrate specificity of thioredoxins and glutaredoxins – towards a functional classification

Abstract

The spatio-temporal reduction and oxidation of protein thiols is an essential mechanism in signal transduction in all kingdoms of life. Thioredoxin (Trx) family proteins efficiently catalyze thiol-disulfide exchange reactions and the proteins are widely recognized for their importance in the operation of thiol switches. Trx family proteins have a broad and at the same time very distinct substrate specificity – a prerequisite for redox switching. Despite of multiple efforts, the true nature for this specificity is still under debate. Here, we comprehensively compare the classification/clustering of various redoxins from all domains of life based on their similarity in amino acid sequence, tertiary structure, and their electrostatic properties. We correlate these similarities to the existence of common interaction partners, identified in various previous studies and suggested by proteomic screenings. These analyses confirm that primary and tertiary structure similarity, and thereby all common classification systems, do not correlate to the target specificity of the proteins as thiol-disulfide oxidoreductases. Instead, a number of examples clearly demonstrate the importance of electrostatic similarity for their target specificity, independent of their belonging to the Trx or glutaredoxin subfamilies.

Shifting paradigms and novel players in Cys-based redox regulation and ROS signaling in plants - and where to go next

“…At present, we encounter a paradigm shift in understanding the redox network by incorporating information on structural properties and electrostatic interfaces of TRXs (Berndt et al 2015;Gellert et al 2019). The authors of the former study compared and clustered 35 TRX-fold domains in 33 proteins.…”

FeS-cluster coordination of vertebrate thioredoxin regulates suppression of hypoxia-induced factor 2α through iron regulatory protein 1

“…Of course, formation of a disulfide needs two cysteinyl residues. The interaction between Trx and a substrate critically depends on complementary electrostatic properties (45,46).…”

Inhibition of microglial receptor‐interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke

“…2,3 Thioredoxin-1 (Trx-1) is a small molecular weight hydrogen donor widely present in cells and exhibits a variety of biological functions, such as antioxidant and anti-inflammatory activities. 15,16 Previous studies have shown that overexpression of Trx-1 provides effective neuroprotective effects on the brain tissue of middle cerebral artery occlusion (MCAO) mice, while inhibition of Trx-1 exacerbates the neuroinflammatory response in MCAO mice. [17][18][19] These findings provide a strong scientific basis for the clinical translational application of Trx-1.…”

“…The inhibition of the inflammatory response following acute phase reperfusion plays an important role in the treatment of cerebral infarction 2,3 . Thioredoxin‐1 (Trx‐1) is a small molecular weight hydrogen donor widely present in cells and exhibits a variety of biological functions, such as antioxidant and anti‐inflammatory activities 15,16 . Previous studies have shown that overexpression of Trx‐1 provides effective neuroprotective effects on the brain tissue of middle cerebral artery occlusion (MCAO) mice, while inhibition of Trx‐1 exacerbates the neuroinflammatory response in MCAO mice 17‐19 .…”