The methionine S-sulfoxide reductase MsrA catalyzes the reduction of methionine sulfoxide, a ubiquitous reaction depending on the thioredoxin system. To investigate interactions between MsrA and thioredoxin (Trx), we determined the crystal structures of yeast MsrA/Mxr1 in their reduced, oxidized, and Trx2-complexed forms, at 2.03, 1.90, and 2.70 Å , respectively. Comparative structure analysis revealed significant conformational changes of the three loops, which form a plastic "cushion" to harbor the electron donor Trx2. The flexible C-terminal loop enabled Mxr1 to access the methionine sulfoxide on various protein substrates. Moreover, the plasticity of the Trx binding site on Mxr1 provides structural insights into the recognition of diverse substrates by a universal catalytic motif of Trx.
Thioredoxins (Trxs)2 are ubiquitous small thiol-disulfide exchange proteins that are involved in many important cellular processes such as reduction of methionine sulfoxide, ribonucleotide, and peroxide (1). These proteins have a highly conserved active site of CXXC motif. During the reaction, the first Cys attacks the intramolecular disulfide bond in the substrate protein, accompanying w ith the formation of an intermolecular disulfide intermediate. This mixed disulfide is subsequently attacked by the second Cys, resulting in release of the reduced substrate protein and the oxidized Trx.