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Protein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation

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  • Henrik M. Hammarén

    (Genome Biology Unit)

  • Eva-Maria Geissen

    (Structural and Computational Biology Unit)

  • Clement M. Potel

    (Genome Biology Unit)

  • Martin Beck

    (Department of Molecular Sociology)

  • Mikhail M. Savitski

    (Genome Biology Unit)

Abstract

Post-translational modifications (PTMs) regulate various aspects of protein function, including degradation. Mass spectrometric methods relying on pulsed metabolic labeling are popular to quantify turnover rates on a proteome-wide scale. Such data have traditionally been interpreted in the context of protein proteolytic stability. Here, we combine theoretical kinetic modeling with experimental pulsed stable isotope labeling of amino acids in cell culture (pSILAC) for the study of protein phosphorylation. We demonstrate that metabolic labeling combined with PTM-specific enrichment does not measure effects of PTMs on protein stability. Rather, it reveals the relative order of PTM addition and removal along a protein’s lifetime—a fundamentally different metric. This is due to interconversion of the measured proteoform species. Using this framework, we identify temporal phosphorylation sites on cell cycle-specific factors and protein complex assembly intermediates. Our results thus allow tying PTMs to the age of the modified proteins.

Suggested Citation

  • Henrik M. Hammarén & Eva-Maria Geissen & Clement M. Potel & Martin Beck & Mikhail M. Savitski, 2022. "Protein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35054-2
    DOI: 10.1038/s41467-022-35054-2
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    1. Sara Cuylen-Haering & Mina Petrovic & Alberto Hernandez-Armendariz & Maximilian W. G. Schneider & Matthias Samwer & Claudia Blaukopf & Liam J. Holt & Daniel W. Gerlich, 2020. "Chromosome clustering by Ki-67 excludes cytoplasm during nuclear assembly," Nature, Nature, vol. 587(7833), pages 285-290, November.
    2. Ana Martinez-Val & Dorte B. Bekker-Jensen & Sophia Steigerwald & Claire Koenig & Ole Østergaard & Adi Mehta & Trung Tran & Krzysztof Sikorski & Estefanía Torres-Vega & Ewa Kwasniewicz & Sólveig Hlín B, 2021. "Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Toby Mathieson & Holger Franken & Jan Kosinski & Nils Kurzawa & Nico Zinn & Gavain Sweetman & Daniel Poeckel & Vikram S. Ratnu & Maike Schramm & Isabelle Becher & Michael Steidel & Kyung-Min Noh & Gio, 2018. "Systematic analysis of protein turnover in primary cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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