Structures of Tryparedoxins Revealing Interaction with Trypanothione
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Birgit Hofmann
Abstract
Tryparedoxins (TXNs) catalyse the reduction of peroxiredoxin type peroxidases by the bisglutathionyl derivative of spermidine, trypanothione, and are relevant to hydroperoxide detoxification and virulence of trypanosomes. The 3Dstructures of the following tryparedoxins are presented: authentic tryparedoxin1 of Crithidia fasciculata, CfTXN1; the histagged recombinant protein, CfTXN1H6; reduced and oxidised CfTXN2, and an alternative substrate derivative of the mutein CfTXN2H6-Cys44Ser. Cys41 (Cys40 in TXN1) of the active site motif 40-WCPPCR-45 proved to be the only solventexposed redox active residue in CfTXN2. In reduced TXNs, its nucleophilicity is increased by a network of hydrogen bonds. In oxidised TXNs it can be attacked by the thiol of the [1]Nglutathionyl residue of trypanothione, as evidenced by the structure of [1]Nglutathionylspermidinederivatised CfTXN2H6-Cys44Ser. Modelling suggests Arg45 (44), Glu73 (72), the Ile110 (109) cisPro111 (110)bond and Arg129 (128) to be involved in the binding of trypanothione to CfTXN2 (CfTXN1). The model of TXNsubstrate interaction is consistent with functional characteristics of known and newly designed muteins (CfTXN2H6-Arg129Asp and Glu73Arg) and the [1]Nglutathionylspermidine binding in the CfTXN2H6-Cys44Ser structure.
Copyright © 2001 by Walter de Gruyter GmbH & Co. KG
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