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

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 1.8A ˚ 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.