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Crystal structures of oxidized and reduced forms of human mitochondrial thioredoxin 2

¹ Unit of Structural Chemistry (CSTR) and ² Laboratory of Cell Biology, Institut des Sciences de la Vie, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium

(RECEIVED June 6, 2005; FINAL REVISION July 19, 2005; ACCEPTED July 22, 2005)

Mammalian thioredoxin 2 is a mitochondrial isoform of highly evolutionary conserved thioredoxins. Thioredoxins are small ubiquitous protein–disulfide oxidoreductases implicated in a large variety of biological functions. In mammals, thioredoxin 2 is encoded by a nuclear gene and is targeted to mitochondria by a N-terminal mitochondrial presequence. Recently, mitochondrial thioredoxin 2 was shown to interact with components of the mitochondrial respiratory chain and to play a role in the control of mitochondrial membrane potential, regulating mitochondrial apoptosis signaling pathway. Here we report the first crystal structures of a mammalian mitochondrial thioredoxin 2. Crystal forms of reduced and oxidized human thioredoxin 2 are described at 2.0 and 1.8 Å resolution. Though the folding is rather similar to that of human cytosolic/nuclear thioredoxin 1, important differences are observed during the transition between the oxidized and the reduced states of human thioredoxin 2, compared with human thioredoxin 1. In spite of the absence of the Cys residue implicated in dimer formation in human thioredoxin 1, dimerization still occurs in the crystal structure of human thioredoxin 2, mainly mediated by hydrophobic contacts, and the dimers are associated to form two-dimensional polymers. Interestingly, the structure of human thioredoxin 2 reveals possible interaction domains with human peroxiredoxin 5, a substrate protein of human thioredoxin 2 in mitochondria.

Keywords: human thioredoxin; X-ray crystal structure; mitochondria; oxidized state; reduced state

Abbreviations: ASK1, apoptosis signal-regulating kinase 1 • TXN, thioredoxin • hTXN1, human cytosolic/nuclear thioredoxin 1 • hTXN2, human mitochondrial thioredoxin 2 • hPRDX5, human peroxiredoxin 5. Gene symbols in this article follow standard nomenclature defined by the Human Genome Organization Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature/). For this reason TXN is used instead of the commonly used Trx for designating thioredoxin in the literature.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051632905.

Reprint requests to: Jean-Paul Declercq, Unit of Structural Chemistry (CSTR), Université catholique de Louvain, 1 place Louis Pasteur, B-1348 Louvain-la-Neuve, Belgium; e-mail: declercq{at}chim.ucl.ac.be; fax: +32-10472707.

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