A building blocks perspective on protein emergence and evolution

Recent findings increasingly suggest the emergence of proteins by mix and match of short peptides, or ‘building blocks’. What are these building blocks, and how did they evolve into contemporary proteins? We review two complementary approaches to tackling these questions. First, a bottom-up approach that involves identifying putative components of primordial peptides, and the synthetic routes through which these peptides may have emerged. Second, searches in protein space to reveal building blocks that make up the contemporary protein repertoire; proteins that are not closely related to one another may nevertheless have certain parts in common, suggesting common ancestry. Identifying such shared building blocks, and characterizing their functions, can shed light on the ancient molecules from which proteins emerged, and hint at the mechanisms that govern their evolution. A key challenge lies in merging these two approaches to create a cohesive narrative of how proteins emerged and continue to evolve.