Did cis- and trans-defensins derive from a common ancestor?
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Defensins are small, cysteine-rich, cationic antimicrobial peptides, serving as effectors of the innate immune system and modulators of the adaptive immune system. They extensively exist in multicellular organisms and are divided into cis and trans according to their disulfide bridge connectivity patterns. It has been proposed that these two types of defensins convergently originated from different ancestors. Here, we report the discovery of a structural signature involved in the formation of the cysteine-stabilized α-helix/β-sheet (CSαβ) fold of the cis-defensins in some trans-β-defensins, with only one amino acid indel (CXC vs. CC. C, cysteine; X, any amino acid). The indel of the X residue in the structural signature provides a possible explanation as to why cis- and trans-defensins possess different folds and connectivity patterns of disulfide bridges formed in evolution. Although our attempt to convert the structure type of a present-day trans-defensin with the X residue deleted was unsuccessful due to the low solubility of the synthetic peptide, a combination of data from structural signature, function, and phylogenetic distribution suggests that these defensins may have descended from a common ancestor. In this evolutionary scenario, we propose that a progenitor cis-scaffold might gradually evolve into a trans-defensin after deleting the X residue in specific lineages. This proposal adds a new dimension to more deeply studying the evolutionary relationship of defensins with different folds and of other distantly related proteins.
KeywordsAntimicrobial peptide Disulfide bridge Structural signature Fold change Evolution
S.Z. conceived and designed the research. W.Z. performed sequence and structural analyses. G.B. performed oxidative refolding experiments of peptides. W.Z., B.G., and S.Z. jointly wrote the paper.
This work was supported by the National Natural Science Foundation of China (Grant Nos. 31870766 and 31570773) to S.Z.
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Conflicts of interest
The authors declare that they have no conflict of interest.
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