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

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Item Type:Article
Title:Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames
Creators Name:Sandmann, C.L. and Schulz, J.F. and Ruiz-Orera, J. and Kirchner, M. and Ziehm, M. and Adami, E. and Marczenke, M. and Christ, A. and Liebe, N. and Greiner, J. and Schoenenberger, A. and Mücke, M.B. and Liang, N. and Moritz, R.L. and Sun, Z. and Deutsch, E.W. and Gotthardt, M. and Mudge, J.M. and Prensner, J.R. and Willnow, T.E. and Mertins, P. and van Heesch, S. and Hubner, N.
Abstract: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.
Keywords:Short ORFs, Microproteins, Short Peptides, Ribosome Profiling, Protein Evolution, De Novo Genes, Primate-Specific Proteins, Protein Interactome, Prisma, Short Linear Motifs, SLiMs
Source:Molecular Cell
Publisher:Cell Press
Page Range:994-1011.e18
Date:16 March 2023
Official Publication:https://doi.org/10.1016/j.molcel.2023.01.023
PubMed:View item in PubMed

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