Molecular and structural aspects controlling the Prdx2 redox-relay

Peroxiredoxins (Prdxs) are peroxidases and they are the major
cellular H2O2 scavengers. Prdxs also regulate H2O2-mediated cell
signaling through thiol-disulfide exchange reactions, also known as
redox-relays. At high cellular H2O2 concentrations, Prdxs can
become hyperoxidized, losing their peroxidase function. Furthermore,
some post-translational modification (PTMs), such as
phosphorylation of specific amino acids, have similar effects on the
Prdx peroxidase function as hyperoxidation. Until now though, it is
not known how PTMs elicit the loss in the peroxidase function nor if
and/or how they affect the redox-relay functionality. Moreover, there
is no information about the structural aspects that determine the
redox-relay functionality of Prdxs. In this project, I focus on
peroxiredoxin 2 (Prdx2) in a redox-relay with the transcription factor
STAT3 which occurs in the presence of a facilitator protein, annexin
A2 (ANXA2). First, I will use cryogenic electron microscopy (cryoEM) to study the structural organization of the Prdx2-STAT3-ANXA2
complex. Second, I will evaluate whether the documented
phosphorylation on Thr89 affects the Prdx2 redox-relay functionality.
Finally, to get a more complete picture of how phosphorylation
changes the structure/function of Prdx2, I will solve the X-ray
structure of a phosphomimetic mutant of Prdx2 (Prdx2 T89D)