Tracing the birth of structural domains from loops during protein evolution

Abstract

The structures and functions of proteins are embedded into the loop scaffolds of structural domains. Their origin and evolution remain mysterious. Here, we use a novel graph-theoretical approach to describe how modular and non-modular loop prototypes combine to form folded structures in protein domain evolution. Phylogenomic data-driven chronologies reoriented a bipartite network of loops and domains (and its projections) into ‘waterfalls’ depicting an evolving ‘elementary functionome’ (EF). Two primordial waves of functional innovation involving founder ‘p-loop’ and ‘winged-helix’ domains were accompanied by an ongoing emergence and reuse of structural and functional novelty. Metabolic pathways expanded before translation functionalities. A dual hourglass recruitment pattern transferred scale-free properties from loop to domain components of the EF network in generative cycles of hierarchical modularity. Modeling the evolutionary emergence of the oldest P-loop and winged-helix domains with AlphFold2 uncovered rapid convergence towards folded structure, suggesting that a folding vocabulary exists in loops for protein fold repurposing and design.

Agency in evolution of biomolecular communication

“…This prediction was experimentally confirmed at different timescales and complexity levels. 21 For example, measuring modularity and hierarchy of evolving networks with statistical descriptors, such as the Newman-Girvan index, the Fast Greedy Community index, and the clustering coefficient, confirmed the rise of hierarchical modularity in networks describing the birth of domains from loops 22,33,47 and of multidomain proteins from a single domain in protein evolution. 34 The biphasic model embodies ancient philosophy.…”

“…32 A recent phylogenomic analysis of predicted structures uncovered the existence of 7078 loop prototypes in the proteomes of 8127 organisms and viruses. 33 prototypes acted as true modular units-engaging in a combinatorial process of recruitment that enhanced functional novelties associated with protein structure. 19 Figure 2B describes how loop prototypes were accreted to form the helix-turn-helix containing the winged helix domain that is central to the process of transcription.…”

“…For example, the Zipf's law of language 69 -a special case of the scale-free distribution-is pervasively present in biological networks, including metabolic, 70 PPI, 71 and domain organization networks. 33 Scale-free patterns explain power law behavior in the occurrence of the Pfam 50 and SCOP 72 domains of proteomes. For example, power law decay values for SCOP domains averaged ∼2 for the proteomes of Bacteria and Archaea and ∼1.4 for the proteomes of Eukarya, 72 which match those for the English and Chinese languages, respectively.…”

“…Figure 2B illustrates accretion with loops—nonregular (aperiodic) loop regions spanning helical and sheet structural components of proteins 32 . A recent phylogenomic analysis of predicted structures uncovered the existence of 7078 loop prototypes in the proteomes of 8127 organisms and viruses 33 . These prototypes were divided into two main subsets.…”

“…Catalogs of elementary units of meaning (lexemes in natural languages) take the form of structural modules accessing different molecular contexts in the course of evolution. Relevant examples of functional meaning include the 1937 modular loop prototypes of proteins 33 indexed in the 190,573 classified loops of the ArchDB (version. 14) structural catalog 52 or the current 5084 families or 2067 superfamilies of domains (holding 1257‐fold structures) cataloged by the SCOPe (release 2.08) gold standard of protein classification 53 .…”