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

Mol Cell. 2023 Mar 16;83(6):994-1011.e18. doi: 10.1016/j.molcel.2023.01.023.

Clara-L Sandmann ¹, Jana F Schulz ¹, Jorge Ruiz-Orera ², Marieluise Kirchner ³, Matthias Ziehm ³, Eleonora Adami ², Maike Marczenke ², Annabel Christ ², Nina Liebe ², Johannes Greiner ², Aaron Schoenenberger ², Michael B Muecke ⁴, Ning Liang ², Robert L Moritz ⁵, Zhi Sun ⁵, Eric W Deutsch ⁵, Michael Gotthardt ⁴, Jonathan M Mudge ⁶, John R Prensner ⁷, Thomas E Willnow ⁸, Philipp Mertins ³, Sebastiaan van Heesch ⁹, Norbert Hubner ¹⁰

Affiliations

1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany.
2 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
3 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Proteomics, 10117 Berlin, Germany.
4 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany; Charité-Universitätsmedizin, 10117 Berlin, Germany.
5 Institute for Systems Biology, Seattle, WA 98109, USA.
6 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
8 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
9 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands. Electronic address: [email protected].
10 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347 Berlin, Germany; Charité-Universitätsmedizin, 10117 Berlin, Germany. Electronic address: [email protected].

PMID: 36806354 DOI: 10.1016/j.molcel.2023.01.023

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

PRISMA; de novo genes; microproteins; primate-specific proteins; protein evolution; protein interactome; ribosome profiling; short ORFs; short linear motifs, SLiMs; short peptides.

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