Abstract
The iron-sulfur (2Fe-2S) binding motif CDGSH appears in many important plant and animal proteins that regulate iron and reactive oxygen metabolism. In human it is found in CISD1-3 proteins involved in diabetes, obesity, cancer, aging, cardiovascular disease and neurodegeneration. Despite the important biological role of the CDGSH domain, its origin, evolution and diversification, are largely unknown. Here, we report that: (1) the CDGSH domain appeared early in evolution, perhaps linked to the heavy use of iron-sulfur driven metabolism by early organisms; (2) a CISD3-like protein with two CDGSH domains on the same polypeptide appears to represent the ancient archetype of CDGSH proteins; (3) the origin of the human CISD3 protein is linked to the mitochondrial endosymbiotic event; (4) the CISD1/2 type proteins that contain only one CDGSH domain, but function as homodimers, originated after the divergence of bacteria and archaea/eukaryotes from their common ancestor; and (5) the human CISD1 and CISD2 proteins diverged about 650–720 million years ago, and CISD3 and CISD1/2 share their descent from an ancestral CISD about 1–1.1 billion years ago. Our findings reveal that the CDGSH domain is ancient in its origin and shed light on the complex evolutionary path of modern CDGSH proteins.
Highlights
The CDGSH domain is part of an iron-sulfur (2Fe-2S) binding motif that appears in several important human proteins e.g., NEET proteins[1,2,3,4,5]
Using a molecular clock analysis we show that the separation of the Class I and Class II eukaryotic CDGSH proteins could be traced to the origins of eukaryotic organisms, and that the human mNT and NAF-1 proteins diverged from their common ancestor ~650–720 million years ago (MYA)
Structural studies conducted on the human CDGSH proteins mNT, NAF-13,12,15,24 and on the human and bacterial CISD3 proteins[2,68], our previous phylogenetic analysis of eukaryotic CISD proteins[1], and our current analysis of these proteins in archaea, bacteria and eukaryotic organisms, reveal an interesting property of CDGSH proteins
Summary
The CDGSH domain is part of an iron-sulfur (2Fe-2S) binding motif that appears in several important human proteins e.g., NEET proteins[1,2,3,4,5]. Perhaps the most important feature of this 3Cys-1His, 2Fe-2S-binding domain, demonstrated for the human CISD1 and CISD2 NEET proteins, is that it is both a relatively stable iron-sulfur binding domain, but at the same time it can participate in different reactions that transfer electrons and/or its entire iron-sulfur cluster to different electron and/or cluster acceptor proteins, respectively[41,42,43,44,45,46,47,48,49,50,51] This feature may explain why the CDGSH domain is highly conserved from bacteria to human. Using a molecular clock analysis we show that the separation of the Class I and Class II eukaryotic CDGSH proteins could be traced to the origins of eukaryotic organisms, and that the human mNT and NAF-1 proteins diverged from their common ancestor ~650–720 million years ago (MYA)
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