The Ascent of Miniproteins

Miniproteins are present across all branches of life and play central roles in diverse biological processes, but their existence fundamentally challenges our assumptions about the minimal sequence, structural, and energetic requirements necessary for protein stability and function. More than molecular curiosities, miniproteins may offer a window into the earliest catalysts that emerged at the origin of life. Here, we focus on metal-containing miniproteins, where coordination chemistry can impart both structural stability and redox activity essential for metabolism. We ask whether primordial peptides could have evolved into complex proteins through miniprotein intermediates by surveying natural miniproteins as snapshots along an evolutionary trajectory, and examining engineered miniproteins that can model the gaps between these snapshots. Finally, we explore whether miniproteins continue to evolve today─either recapitulating early evolutionary processes or giving rise to entirely new folds and functions.