Primordial emergence of a nucleic acid-binding protein via phase separation and statistical ornithine-to-arginine conversion

Liam M. Longo, Dragana Despotović, Orit Weil-Ktorza, Matthew J. Walker, Jagoda Jabłońska, Yael Fridmann-Sirkis, Gabriele Varani, Norman Metanis*, Dan S. Tawfik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


De novo emergence demands a transition from disordered polypeptides into structured proteins with well-defined functions. However, can polypeptides confer functions of evolutionary relevance, and how might such polypeptides evolve into modern proteins? The earliest proteins present an even greater challenge, as they were likely based on abiotic, spontaneously synthesized amino acids. Here we asked whether a primordial function, such as nucleic acid binding, could emerge with ornithine, a basic amino acid that forms abiotically yet is absent in modern-day proteins. We combined ancestral sequence reconstruction and empiric deconstruction to unravel a gradual evolutionary trajectory leading from a polypeptide to a ubiquitous nucleic acid-binding protein. Intermediates along this trajectory comprise sequence-duplicated functional proteins built from 10 amino acid types, with ornithine as the only basic amino acid. Ornithine side chains were further modified into arginine by an abiotic chemical reaction, improving both structure and function. Along this trajectory, function evolved from phase separation with RNA (coacervates) to avid and specific double-stranded DNA binding. Our results suggest that phase-separating polypeptides may have been an evolutionary resource for the emergence of early proteins, and that ornithine, together with its postsynthesis modification to arginine, could have been the earliest basic amino acids.

Original languageAmerican English
Pages (from-to)15731-15739
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - 7 Jul 2020

Bibliographical note

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  • Abiotic amino acids
  • Helix-hairpin-helix
  • Prebiotic chemistry
  • Protein evolution
  • Protein synthesis


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