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

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

doi:10.1016/j.molcel.2023.01.023

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

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. WillnowPhilipp Mertins, Sebastiaan van Heesch^*, Norbert Hubner^*

^*Corresponding author for this work

Department of Biomedicine - Forskning og uddannelse, Skou-bygningen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Molecular Cell
Volume	83
Issue	6
Pages (from-to)	994-1011.e18
ISSN	1097-2765
DOIs	https://doi.org/10.1016/j.molcel.2023.01.023
Publication status	Published - Mar 2023

Keywords

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

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Sandmann, C. L., Schulz, J. F., Ruiz-Orera, J., Kirchner, M., Ziehm, M., Adami, E., Marczenke, M., Christ, A., Liebe, N., Greiner, J., Schoenenberger, A., Muecke, M. B., Liang, N., Moritz, R. L., Sun, Z., Deutsch, E. W., Gotthardt, M., Mudge, J. M., Prensner, J. R., ... Hubner, N. (2023). Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames. Molecular Cell, 83(6), 994-1011.e18. https://doi.org/10.1016/j.molcel.2023.01.023

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

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

author = "Sandmann, {Clara L.} and Schulz, {Jana F.} and Jorge Ruiz-Orera and Marieluise Kirchner and Matthias Ziehm and Eleonora Adami and Maike Marczenke and Annabel Christ and Nina Liebe and Johannes Greiner and Aaron Schoenenberger and Muecke, {Michael B.} and Ning Liang and Moritz, {Robert L.} and Zhi Sun and Deutsch, {Eric W.} and Michael Gotthardt and Mudge, {Jonathan M.} and Prensner, {John R.} and Willnow, {Thomas E.} and Philipp Mertins and {van Heesch}, Sebastiaan and Norbert Hubner",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = mar,

doi = "10.1016/j.molcel.2023.01.023",

language = "English",

volume = "83",

pages = "994--1011.e18",

journal = "Molecular Cell",

issn = "1097-2765",

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Sandmann, CL, Schulz, JF, Ruiz-Orera, J, Kirchner, M, Ziehm, M, Adami, E, Marczenke, M, Christ, A, Liebe, N, Greiner, J, Schoenenberger, A, Muecke, MB, Liang, N, Moritz, RL, Sun, Z, Deutsch, EW, Gotthardt, M, Mudge, JM, Prensner, JR, Willnow, TE, Mertins, P, van Heesch, S & Hubner, N 2023, 'Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames', Molecular Cell, vol. 83, no. 6, pp. 994-1011.e18. https://doi.org/10.1016/j.molcel.2023.01.023

Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames. / Sandmann, Clara L.; Schulz, Jana F.; Ruiz-Orera, Jorge et al.
In: Molecular Cell, Vol. 83, No. 6, 03.2023, p. 994-1011.e18.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

AU - Sandmann, Clara L.

AU - Schulz, Jana F.

AU - Ruiz-Orera, Jorge

AU - Kirchner, Marieluise

AU - Ziehm, Matthias

AU - Adami, Eleonora

AU - Marczenke, Maike

AU - Christ, Annabel

AU - Liebe, Nina

AU - Greiner, Johannes

AU - Schoenenberger, Aaron

AU - Muecke, Michael B.

AU - Liang, Ning

AU - Moritz, Robert L.

AU - Sun, Zhi

AU - Deutsch, Eric W.

AU - Gotthardt, Michael

AU - Mudge, Jonathan M.

AU - Prensner, John R.

AU - Willnow, Thomas E.

AU - Mertins, Philipp

AU - van Heesch, Sebastiaan

AU - Hubner, Norbert

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - de novo genes

KW - microproteins

KW - primate-specific proteins

KW - PRISMA

KW - protein evolution

KW - protein interactome

KW - ribosome profiling

KW - short linear motifs, SLiMs

KW - short ORFs

KW - short peptides

UR - http://www.scopus.com/inward/record.url?scp=85149990875&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2023.01.023

DO - 10.1016/j.molcel.2023.01.023

M3 - Journal article

C2 - 36806354

AN - SCOPUS:85149990875

SN - 1097-2765

VL - 83

SP - 994-1011.e18

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

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

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