Functional emergence driven by structural evolution of the <scp>DSBH</scp> domain in Fe ²⁺ and α‐ketoglutarate‐dependent family

Ten-eleven translocation (TET), AlkB homolog (ALKBH), and histone lysine demethylase (KDM) proteins belong to the 2-oxoglutarate (2OG) and ferrous iron-dependent oxygenases, which catalyze substrates spanning the entire central dogma (DNA-RNA-Protein). It serves as a model for understanding how functional diversity is shaped by structural changes within the central dogma. The evolutionary characteristics of the core catalytic domain double-stranded β-helix (DSBH) are the main reasons for their specific substrate recognition ability. Nonetheless, the structural biological explanations remain ambiguous. Here, we constructed the sequence evolutionary tree of the full-length and DSBH catalytic domains from seven prevalent mammalian species. The DSBH domain evolutionary trajectory was generated by multispecies structure fitting and mapping. Taking humans as a reference, the relationships among the three subfamilies, KDM, ALKBH, and TET, were depicted. In conjunction with the evolutionary tree and domain map, this method analyzed the emergence and extinction of α-helix and β-sheet structures and length variations in pivotal regions to ascertain the structural history of DSBH domains across subfamilies. Furthermore, reduced amino acid analysis and prospective mapping were utilized to investigate the correlation between the structural progression and functional assessment of the DSBH structure. A new perspective has arisen, highlighting variations in the proregion of the DSBH domain as essential for its particular substrate recognition function, as this domain determines the binding conditions for protein substrates. This provides a new angle for understanding the evolution of proteins from simple structures to complex functions and leads to new advances for the bioengineering field.