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The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 (CAP) superfamily represents one of the most widely recruited molecular scaffolds in animal venoms. Despite their ubiquity, the evolutionary forces shaping their diversification are still mostly unknown. Here, we integrate Bayesian and maximum-likelihood phylogenetics with site- and branch-level selection analyses (FUBAR, MEME, CodeML, and BUSTED) to investigate CAP evolution across 12 venomous metazoan lineages, spanning insects, arachnids, centipedes, lizards, and snakes. Our results reveal a spectrum of evolutionary regimes, with purifying selection dominating across arthropods, whereas episodic and pervasive positive selection strongly shape CAP diversification in toxicoferan reptiles. Exceptional diversification was also detected in triatomine bugs and Ixodes ticks, suggesting host-driven lineage-specific adaptive pressures. Three-dimensional representations show that diversification frequently targets exposed and functionally relevant residues, supporting coevolutionary arms race scenarios. Altogether, our findings demonstrate that CAP proteins have undergone multiple recurrent trajectories of molecular innovation, reflecting the convergent interplay between ecology, structure, and lineage-specific pressures. This study establishes a comprehensive framework for understanding how a single ancestral protein scaffold has been repeatedly co-opted and diversified across the animal kingdom's chemical arsenals. Additionally, we describe a hybrid loop-β-sheet extension of the CAP1 motif based on sequence and structural conservation evidence across CAP proteins.
Mancuso et al. (2026) studied this question.