Structural determinants of multimerization and dissociation in 2-Cys peroxiredoxin chaperone function

Abstract

Peroxiredoxins (PRDXs) are abundant peroxidases present in all kingdoms of life. Recently, they have been shown to also carry out additional roles as molecular chaperones. To address this emerging supplementary function, this review focuses on structural studies of 2-Cys PRDX systems exhibiting chaperone activity. We provide a detailed understanding of the current knowledge of structural determinants underlying the chaperone function of PRDXs. Specifically, we describe the mechanisms which may modulate their quaternary structure to facilitate interactions with client proteins and how they are coordinated with the functions of other molecular chaperones. Following an overview of PRDX molecular architecture, we outline structural details of the presently best-characterized peroxiredoxins exhibiting chaperone function and highlight common denominators. Finally, we discuss the remarkable structural similarities between 2-Cys PRDXs, small HSPs, and J-domain-independent Hsp40 holdases in terms of their functions and dynamic equilibria between lowand high-molecular-weight oligomers. ll

Spatial and temporal control of mitochondrial H 2 O 2 release in intact human cells

“…It is currently unclear why this should be so, although speculatively it could relate to conservation of NADPH. It is also unclear why peroxiredoxins are apparently present at much higher amounts than is necessary for H 2 O 2 scavenging, although perhaps this relates to their other functions, for example as molecular chaperones (Rhee & Woo, 2020; Troussicot et al , 2021). In summary, the rate‐limiting step for cytosolic H 2 O 2 handling and thus cytosolic detection of mitochondria‐generated H 2 O 2 appears to be in the capacity to reduce PRDXs.…”

Peroxiredoxin, Senescence, and Cancer

“…Interestingly, peroxiredoxin homodimers may assemble to form a toroidal complex of 8, 10, or 12 subunits. The change in their quaternary structure regulates their functional switch from peroxidase to chaperone [ 43 ]. These toroid structures can stack with one another to form high molecular weight (HMW) nanotube-like structures or dodecahedron [ 44 ].…”

Impact of Hydrogen Peroxide on Protein Synthesis in Yeast

“…Peroxiredoxins use reactive cysteine amino acids to decompose hydrogen peroxide, to regulate cellular signaling by transducing hydrogen peroxide signals and to bind to misfolded proteins (via their chaperone function [20,21]). In yeast, there are five peroxiredoxins (Prx), three of which are cytoplasmic (Tsa1, Tsa2 and Ahp1), one nuclear (Dot5) and one 1-Cys peroxiredoxin which functions in the mitochondria, Prx1 [22].…”

“…High levels of H 2 O 2 can cause hyperoxidation into a sulfinic form (Cys-SO 2 H) that stabilizes a high-molecular-weight (HMW) complex and inactivation of the peroxidase function. The HMW form has been associated with a functional switch of the enzyme into a chaperone holdase activity, that seems to be modulated also by its dissociation via sulfiredoxin, Srx1 [21]. Persistently elevated H 2 O 2 levels transform Prx catalytic cysteines into an irreversible sulfonic acid form (Cys-SO 3 H), also multimerizing into a HMW form.…”