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FeS-cluster coordination of vertebrate thioredoxins regulates suppression of hypoxia-induced factor 2α through iron regulatory protein 1
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.04.235721v1?rss=1
Authors: Berndt, C., Hanschmann, E.-M., Urbainsky, C., Jordt, L. M., Mueller, C. S., Bodnar, Y., Schippers, S., Handorf, O., Nowack, R., Moulis, J.-M., Schulzke, C., Schuenemann, V., Lillig, C. H.
Abstract:
Thioredoxins (Trxs) provide electrons to essential cellular processes such as DNA synthesis. Here, we characterize human and murine Trx1 as new iron-sulfur proteins. The [2Fe-2S] cluster is complexed using cysteinyl side chains 32 and 73 in a dimeric holo-complex. Formation of the holo-dimer depends on small structural changes of the loop connecting helices three and four and is stabilized by the formation of a direct electrostatic interaction between Lys72 and Asp60 of two monomers. The not strictly conserved Cys73 in vertebrates co-evolved with the regulation of cellular iron homeostasis through the iron-regulatory proteins (IRP). Active apo-Trx1 is required for the reduction of cysteinyl residues in IRP1 and its binding to the iron-responsive elements in the mRNA encoding hypoxia-inducible factor (HIF) 2. Depletion of Trx1 increased the mRNA levels of HIF2, an important target of IRP1. Hence, translation of the HIF2 mRNA requires either sufficient iron-supply or the lack of reducing power of the Trx system under iron-limiting conditions. Only then, HIF2 protein may accumulate under hypoxic conditions to transcriptionally regulate processes like erythropoiesis.
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By Multimodal LLCLink to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.08.04.235721v1?rss=1
Authors: Berndt, C., Hanschmann, E.-M., Urbainsky, C., Jordt, L. M., Mueller, C. S., Bodnar, Y., Schippers, S., Handorf, O., Nowack, R., Moulis, J.-M., Schulzke, C., Schuenemann, V., Lillig, C. H.
Abstract:
Thioredoxins (Trxs) provide electrons to essential cellular processes such as DNA synthesis. Here, we characterize human and murine Trx1 as new iron-sulfur proteins. The [2Fe-2S] cluster is complexed using cysteinyl side chains 32 and 73 in a dimeric holo-complex. Formation of the holo-dimer depends on small structural changes of the loop connecting helices three and four and is stabilized by the formation of a direct electrostatic interaction between Lys72 and Asp60 of two monomers. The not strictly conserved Cys73 in vertebrates co-evolved with the regulation of cellular iron homeostasis through the iron-regulatory proteins (IRP). Active apo-Trx1 is required for the reduction of cysteinyl residues in IRP1 and its binding to the iron-responsive elements in the mRNA encoding hypoxia-inducible factor (HIF) 2. Depletion of Trx1 increased the mRNA levels of HIF2, an important target of IRP1. Hence, translation of the HIF2 mRNA requires either sufficient iron-supply or the lack of reducing power of the Trx system under iron-limiting conditions. Only then, HIF2 protein may accumulate under hypoxic conditions to transcriptionally regulate processes like erythropoiesis.
Copy rights belong to original authors. Visit the link for more info