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Notes:
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Grx5 is a Saccharomyces cerevi-
siae glutaredoxin involved in iron-sulfur cluster
(FeSC) biogenesis. Previous work suggests that Grx5
is involved in regulating protein cysteine glutathio-
nylation, prompting several questions about the
systemic role of Grx5. First, is the regulation of
mixed protein-glutathione disulfide bridges in FeSC
biosynthetic proteins by Grx5 sufficient to account
for the observed phenotypes of the ⌬grx5 mutants?
If so, does Grx5 regulate the oxidation state of mixed
protein-glutathione disulfide bridges in FeSC bio-
genesis in general? Alternatively, can the ⌬grx5
mutant phenotypes be explained if Grx5 acts on just
one or a few of the FeSC biogenesis proteins?
In the first part of this article, we address these
questions by building and analyzing a mathematical
model of FeSC biosynthesis. We show that, indepen-
dent of the tested parameter values, the dynamic
behavior observed in cells depleted of Grx5 can only
be qualitatively reproduced if Grx5 acts by regulat-
ing the initial assembly of FeSC in scaffold proteins.
This can be achieved by acting on the cysteine
desulfurase (Nfs1) activity and/or on scaffold func-
tionality.
In the second part of this article, we use structural
bioinformatics methods to evaluate the possibility
of interaction between Grx5 and proteins involved
in FeSC biogenesis. Based on such methods, our
results indicate that the proteins with which Grx5 is
more likely to interact are consistent with the ki-
netic modeling results.
Thus, our theoretical studies, combined with
known Grx5 biochemistry, suggest that Grx5 acts on
FeSC biosynthesis by regulating the redox state of
important cysteine residues in Nfs1 and/or in the
scaffold proteins where FeSC initially assemble. |
