Structures of the germline-specific Deadhead and Thioredoxin T proteins from Drosophila melanogaster reveal unique features among Thioredoxins

Abstract

ABSTRACTThioredoxins (Trxs) are ubiquitous enzymes that regulate the redox state in cells. In Drosophila, there are two germline-specific Trxs, Deadhead (Dhd) and TrxT. Both proteins belong to the L(3)mbt malignant brain tumor signature and to the MMS survival network of genes that mediate the cellular response to DNA damage. Dhd is a maternal protein required for early embryogenesis that promotes protamine-histone exchange in fertilized eggs and midblastula transition. TrxT is testis-specific and associates with the lampbrush loops of the Y chromosome.Here we present the first structures of Dhd and TrxT that unveil new features of these Thioredoxins. Dhd is highly positively charged, unusual in canonical Trxs. This positively charged surface can facilitate its approximation to DNA and to protamine oligomers, to promote chromatin remodeling. On the other hand, TrxT contains a C-terminal extension, mostly unstructured and highly flexible, which wraps the conserved core through a closed conformation. This extension partially covers the catalytic site and modulates the redox activity of the protein.The information provided by these structures can guide future work aimed at understanding how redox inputs modulate the initial steps of embryo development in Drosophila and may help in the design of molecular inhibitors through a structure-based approach.HighlightsWe have determined the first structures of the germline-specific Trxs Dhd and TrxT.Dhd has a highly positively charged surface that facilitates its approximation to DNA and protamine oligomers, to promote chromatin remodeling.TrxT contains a C-terminal extension, highly unusual in canonical Trxs, mostly unstructured and highly flexible.The TrxT C-terminal extension partially covers the catalytic site and modulates the redox activity of the protein.The differences observed in Thioredoxins can help in fine-tuning specific molecules to be active against selected insect species.