The evolution of metalloproteins

A new perspective on the evolution of metalloproteins. In his latest paper dr Kevin Waldron presents his research concerning the evolution of metal ion binding by superoxide dismutases. The results show that the dismutases display high evolutionary flexibility in their ion preferences, which has allowed them to switch their preferences between iron and manganese as cofactors multiple times during evolution. These results may change our views on the evolution of all metalloproteins – they suggest that metal cofactor preferences may be more flexible than previously appreciated. We are pleased to inform that the study has been published in the prestigious journal Nature Ecology and Evolution.
Dr Kevin Waldron joined IBB PAS in December 2022 as the leader of the newly formed Laboratory of Metalloprotein Biology. For his research, he secured funding from the National Science Centre (MAESTRO grant) and from the National Institute of Health (USA).
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Dr Waldron’s comments

In our latest paper, we have combined detailed bioinformatic analyses of genome and protein sequences with classical methods of biochemistry and structural biology to study the evolution of a metalloenzyme family, the iron (Fe) or manganese (Mn) dependent superoxide dismutases (SodFM). Members of this protein family were traditionally considered to be ‘specific’ for either Fe or Mn as their essential cofactor for catalyzing their reaction, which is pivotal in the detoxification of the reactive oxygen species, superoxide. Only a limited few SodFMs were known to be ‘cambialistic’, i.e. able to catalyse their reaction using either metal. Here, we categorized the SodFM family into five discrete subfamilies. We sampled and characterized the metal-preference of >60 SodFM isozymes from across the phylogenetic tree, including multiple enzymes from each of the five subfamilies. This biochemical analysis demonstrated that phylogenetics do not perfectly correlate with metal-preference, with each subfamily containing members of varying preferences. By studying discrete regions of the phylogenetic tree, we identified several specificity switches that have occurred during evolution, with Mn-preferring enzymes evolving to gain the function of catalysis with Fe, or vice versa. Through extensive mutagenesis studies, we demonstrated a role in this evolutionary switching of metal-preference for two key residues. These amino acids are localized within the metal’s secondary coordination sphere, lying in close spatial proximity to the metal but making no direct contacts with it. Together, this study has demonstrated that metal-preference in the SodFM family is highly fluid; it can and does change frequently, and these changes can be mediated by mutations at just two loci. Furthermore, it suggests that metal cofactor preferences in metalloenzymes more broadly may be more flexible than previously appreciated, with potential implications for our understanding of the function and evolution of many more of the approximately half of all enzymes that require an essential metal cofactor to function.