Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

Bibliographic Collection: 
Publication Type: Journal Article
Authors: Clara-L. Sandmann; Jana F. Schulz; Jorge Ruiz-Orera; Marieluise Kirchner; Matthias Ziehm; Eleonora Adami; Maike Marczenke; Annabel Christ; Nina Liebe; Johannes Greiner; Aaron Schoenenberger; Michael B. Muecke; Ning Liang; Robert L. Moritz; Zhi Sun; Eric W. Deutsch; Michael Gotthardt; Jonathan M. Mudge; John R. Prensner; Thomas E. Willnow; Philipp Mertins; Sebastiaan van Heesch; Norbert Hubner
Year of Publication: 2023
Publication Language: eng

All species continuously evolve short open reading frames (sORFs) that can be templated for protein synthesis and may provide raw materials for evolutionary adaptation. We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids—all of which are smaller than the smallest human microprotein annotated to date. To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass-spectrometry-based interactome screen with motif resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins, thereby helping to elucidate this underexplored territory of the human proteome.