Manuscript Accepted to PNAS
Related Publication
Primordial emergence of a nucleic acid-binding protein via phase separation and statistical ornithine-to-arginine conversion↗By Liam M. Longo^, Dragana Despotović^, Orit Weil-Ktorza^, Matthew J. Walker, Jagoda Jabłońska, Yael Fridmann-Sirkis, Gabriele Varani, Norman Metanis*, and Dan S. Tawfik*
The first proteins emerged some 4 billion years ago, and understanding how they came about is a daunting challenge. Further complicating matters, the rules of protein structure and function derived from modern proteins may be irrelevant to their earliest ancestors. We report an integrated approach in which protein sequence, structure, and function are considered. We show that a simple function (phase separation) may have served as the basis for a complex function (specific double-stranded DNA binding), and that disordered polypeptides can give rise to structured, well-packed domains. Finally, we demonstrate that functional proteins may arise from short and simple sequences that include ornithine, an amino acid likely present in early proteins yet absent in modern proteins.