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Fission or fusion? A story of protein evolution

The quest for common ancestors of different multiheme cytochromes c sheds new light in the coevolution of life and Earth.

The chemical components that make up living organisms and their byproducts never disappear. They are continuously recycled through processes called biogeochemical cycles, crucial for the evolution of life on Earth as we know it. A group of proteins involved in electron transport networks, multiheme cytochromes c (MHC), play key roles in these diverse biogeochemical cycles, including those of nitrogen, sulfur, and iron. A team of researchers from ITQB NOVA, INIAV and the University of Florence now unveils a bit more about the evolution of these proteins, opening new perspectives about the interplay between biology and geochemistry across large time scales in the history of Earth.

Over time, genes can suffer rearrangements, either by fusion with other genes, or by fission into several parts - two crucial mechanisms in the evolutionary history of the species. A study now published in Molecular Biology and Evolution shows that fission mechanisms also drive the evolution of MHCs and not only gene fusion events, as previous studies proposed.

In our family, because of genetics, we can share similarities with distant cousins, reflecting our common origin. The same happens with the families of proteins. In this case, “some MHCs families share sequence and structural similarities, such as the presence of repetitive modules, which reflects a common ancestral origin”, says Claudia Andreini, from the University of Florence. Combined with other methods, researchers performed a phylogenetic analysis with different MHCs to understand the evolution of these proteins through genetic changes and their evolutionary relationships.

The results have shown that two of the studied MHCs, NrfA (pentaheme nitrite reductase) and cyt c554 (tetraheme cytochrome c554), belong to different clades. “It is as if they belonged to different branches of the family tree. You must go back to find a common ancestral”, explains Ricardo Louro, ITQB NOVA researcher and corresponding author of the study. This suggests that these two MHCs result from truncation events, which means they are different and shorter versions of the original proteins, an ancestral ONR (octaheme nitrite reductase) and MccA (copper-containing sulfite reductase), respectively.


Evolution of MHCs in different clades and the Last Common Ancestor (LCA) in the root.

The study also shows that the common ancestor of the multiheme cytochromes c analyzed was likely an octaheme cytochrome (a cytochrome with eight heme groups), similar to extant IhOCC capable of nitrite reduction. The evolution from this ancestral protein included events such as natural pruning and grafting of heme-binding polypeptide modules, meaning these were removed and added in a rearranged form, according to the physiological needs of the organisms. This led to the emergence of the extant MHCs that catalyze very distinct reactions within the nitrogen, sulfur, and iron biogeochemical cycles.

“The previous studies lacked a phylogenetic analysis with a combination of structural and sequence information, and an unbiased root placement method. Our study combines these criteria with minimal functional-site characterization of the hemes to refine the previous evolutionary proposals”, adds Ricardo Soares, working at INIAV, PhD student at ITQB NOVA and the first author of the work.

For the first time, the root was not considered a priori in the analysis but rather found through calculations. “This opens up the opportunity to study all other families of MHC in this new light, work that we are now pursuing”, concludes Ricardo Louro.


Original Paper

Molecular Biology and Evolution

A New Paradigm of Multiheme Cytochrome Evolution by Grafting and Pruning Protein Modules

Ricardo Soares, Nazua L. Costa, Catarina M. Paquete, Claudia Andreini and Ricardo O. Louro


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