# From hemocuprein to CSRP: the many faces of Cu/Zn superoxide dismutase

## TL;DR

This paper explores how the Cu/Zn superoxide dismutase enzyme evolved into various forms across species, including fungi and animals, and how these forms contribute to biological functions like virulence and tissue regeneration.

## Contribution

The paper provides a comprehensive review of the evolutionary diversification and functional adaptations of Cu/Zn SOD derivatives in eukaryotes.

## Key findings

- Cu/Zn SOD derivatives like CCS, fungal Cu-only SODs, and animal CSRP have evolved unique biophysical and functional properties.
- Cu-only SODs promote fungal virulence, while amphibian CSRP is linked to tissue regeneration involving reactive oxygen species.
- These SOD derivatives have adapted to function outside the cell with reduced metal-binding affinities.

## Abstract

From bacteria to humans, the highly conserved Cu- and Zn-containing superoxide dismutase (Cu/Zn SOD) plays a pivotal role in free radical biology. By using Cu to disproportionate superoxide at rates that approach diffusion limits, Cu/Zn SODs are premier antioxidants. Interestingly, during eukaryotic evolution, several derivatives of the Cu/Zn SOD polypeptide appeared, where the Cu and/or Zn sites were lost and in some cases, Cu/Zn SOD-like sequences were replicated or fused to other protein domains. Such variations of Cu/Zn SOD include the CCS Cu chaperone, fungal Cu-only SODs, and animal CSRP (Cu-only SOD repeat proteins). Here we review the unique biophysical properties and biological functions of these Cu/Zn SOD-like proteins. CCS appeared early in eukaryotic evolution, where a primordial Cu/Zn SOD lost its Cu site and was fused to other Cu-binding domains, creating a dual Cu/molecular chaperone for intracellular Cu/Zn SOD. In the Opisthokont supergroup of eukaryotes that formed fungi and animals, a Cu/Zn SOD lost its Zn binding capacity and structural loop VII, forming Cu-only SODs of fungi and tandemly amplified Cu-only SODs in animal CSRP. Cu-only SODs and Cu-binding CSRPs are efficient SODs, and with lowered Cu-binding affinities, they have evolved to function exclusively outside the cell. Cu-only SODs promote virulence of pathogenic fungi, and recent studies have implicated a role for amphibian CSRP in tissue regeneration, a process involving reactive oxygen species. We have just begun to understand how nature has diversified the Cu/Zn SOD template to create new molecules for metal and free radical biology.

Graphical AbstractModel showing derivatives of Cu/Zn SOD in eukaryotes including the CCS copper chaperone, fungal Cu-only SODs and animal CSRP (Cu-only SOD repeat proteins)

Model showing derivatives of Cu/Zn SOD in eukaryotes including the CCS copper chaperone, fungal Cu-only SODs and animal CSRP (Cu-only SOD repeat proteins)