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Despite their very close structural similarity, CxxC/S-type (class I) glutaredoxins (Grxs) actas oxidoreductases, while CGFS-type (class II) Grxs act as FeS cluster transferases. Here weshow that the key determinant of Grx function is a distinct loop structure adjacent to theactive site. Engineering of a CxxC/S-type Grx with a CGFS-type loop switched its functionfrom oxidoreductase to FeS transferase. Engineering of a CGFS-type Grx with a CxxC/S-typeloop abolished FeS transferase activity and activated the oxidative half reaction of the oxi-doreductase. The reductive half-reaction, requiring the interaction with a second GSHmolecule, was enabled by switching additional residues in the active site. We explain howsubtle structural differences, mostly depending on the structure of one particular loop, act inconcert to determine Grx function.
The failure of insulin-producingβ-cells is the underlying cause of hyperglycemia in diabetes mellitus.β-cell decay has been linked to hypoxia, chronic inflammation,and oxidative stress. Thioredoxin (Trx) proteins are major actors in redox signaling and essential for signal transduction and the cellular stress response. We haveanalyzed the cytosolic, mitochondrial, and extracellular Trx system proteins in hypoxic and cytokine-induced stress usingβ-cell culture, isolated pancreatic islets, andpancreatic islet transplantation modelling low oxygen supply.Protein levels of cytosolic Trx1 and Trx reductase (TrxR) 1 significantly decreased, while mitochondrial Trx2 and TrxR2 increased upon hypoxia and reox-ygenation. Interestingly, Trx1 was secreted byβ-cells during hypoxia. Moreover, murine and human pancreatic islet grafts released Trx1 upon glucose stimulation.Survival of transplanted islets was substantially impaired by the TrxR inhibitor auranofin.Since a release was prominent upon hypoxia, putative paracrine effects of Trx1 onβ-cells were examined. In fact, exogenously added recombinant hTrx1 mitigatedapoptosis and preserved glucose sensitivity in pancreatic islets subjected to hypoxia and inflammatory stimuli, dependent on its redox activity. Human subjects werestudied, demonstrating a transient increase in extracellular Trx1 in serum after glucose challenge. This increase correlated with better pancreatic islet function.Moreover, hTrx1 inhibited the migration of primary murine macrophages.In conclusion, our study offers evidence for paracrine functions of extracellular Trx1 that improve the survival and function of pancreaticβ-cells.