Universal and Lineage-Specific Patterns in the Distribution of ECOD Domain Homology Groups Across Superkingdoms.

Proteins are built from modular domains that serve as fundamental units of structure and evolution. While individual domains have been extensively cataloged, their collective distribution across the lineages of life has remained poorly resolved. Here, we use the Evolutionary Classification of Protein Domains (ECOD) to chart the occurrence of domain homology groups (H-groups) across 44 model proteomes representing Eukaryota, Bacteria, and Archaea, in which 1.16 million domains are assigned to 3320 H-groups. H-groups are categorized as universal (occupying all three superkingdoms), shared between superkingdoms, or lineage-specific. The fold architecture distributions were examined: α/β sandwiches and other mixed architectures were abundant in universal H-groups, whereas α-rich architectures are expanded in eukaryotic H-groups and β-rich folds in bacterial H-groups. 126 (3.8%) H-groups occur in all organisms, forming a universal structural core that supports central processes of energy conversion, metabolism, and information flow. These widely distributed folds coincide with canonical superfolds-robust, adaptable architectures repeatedly repurposed for key biochemical roles. Two superkingdom groups trace evolutionary connections between lineages: bacterial metabolic and chaperone systems inherited by eukaryotes, archaeal informational machinery conserved in eukaryotic nuclei, and ancient redox scaffolds linking bacteria and archaea. Lineage-exclusive domains, in turn, highlight distinct adaptive strategies-regulatory and cytoskeletal innovation in eukaryotes, envelope and motility specialization in bacteria, and redox or replication refinements in archaea. Together, these data provide a quantitative, structure-based view of protein domain evolution across the tree of life, showing that the essential architecture of life relies on a conserved set of ancient folds, while lineage-specific diversity has largely arisen through the recombination and functional diversification of pre-existing domains.