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Molecular & Cellular Proteomics

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Multi-omics Characterization of Interaction-mediated Control of Human Protein Abundance levels

View ORCID ProfileAbel Sousa, View ORCID ProfileEmanuel Gonçalves, Bogdan Mirauta, View ORCID ProfileDavid Ochoa, Oliver Stegle and Pedro Beltrao  Correspondence email
Molecular & Cellular Proteomics August 9, 2019, First published on June 25, 2019, 18 (8 suppl 1) S114-S125; https://doi.org/10.1074/mcp.RA118.001280
Abel Sousa
‡Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3s), Rua Alfredo Allen 208, 4200–135, Porto, Portugal§Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200–135, Porto, Portugal¶Graduate Program in Areas of Basic and Applied Biology (GABBA), Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050–313, Porto, Portugal‖European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK
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  • ORCID record for Abel Sousa
Emanuel Gonçalves
**Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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  • ORCID record for Emanuel Gonçalves
Bogdan Mirauta
‖European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK
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David Ochoa
‖European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK
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Oliver Stegle
‖European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK‡‡European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany§§Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
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Pedro Beltrao
‖European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK
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  • For correspondence: pbeltrao@ebi.ac.uk
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Graphical Abstract

Figure1
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Highlights

  • Up to ∼40% of proteins have copy-number changes attenuated, likely via degradation.

  • Interaction-dependent protein attenuations correlates with interface size.

  • Protein attenuation is reflected in variation in protein levels in normal tissues.

  • Protein attenuation buffers expression differences due to natural genetic variation.

Abstract

Proteogenomic studies of cancer samples have shown that copy-number variation can be attenuated at the protein level for a large fraction of the proteome, likely due to the degradation of unassembled protein complex subunits. Such interaction-mediated control of protein abundance remains poorly characterized. To study this, we compiled genomic, (phospho)proteomic and structural data for hundreds of cancer samples and find that up to 42% of 8,124 analyzed proteins show signs of post-transcriptional control. We find evidence of interaction-dependent control of protein abundance, correlated with interface size, for 516 protein pairs, with some interactions further controlled by phosphorylation. Finally, these findings in cancer were reflected in variation in protein levels in normal tissues. Importantly, expression differences due to natural genetic variation were increasingly buffered from phenotype differences for highly attenuated proteins. Altogether, this study further highlights the importance of posttranscriptional control of protein abundance in cancer and healthy cells.

  • Proteogenomics
  • Cancer Biology
  • Bioinformatics
  • Computational Biology
  • Posttranslational Modifications

Footnotes

  • Author contributions: A.S., E.G., B.M., and P.B. designed research; A.S. performed research; D.O. contributed new reagents/analytic tools; O.S. provided ideas and supervision; A.S., E.G., and B.M. analyzed data; and A.S., B.M., and P.B. wrote the paper.

  • ↵* The authors declare that they have no conflict of interest.

  • ↵Embedded Image This article contains supplemental material Tables 1–4 and Figs. S1–S7.

  • 1 The abbreviations used are:

    CNV
    copy-number variation
    TCGA
    The Cancer Genome Atlas
    CPTAC
    Cancer Clinical Proteomics Research
    CCLE
    Cancer Cell Line Encyclopedia
    GISTIC
    Genomic Identification of Significant Targets in Cancer
    CORUM
    comprehensive resource of mammalian protein complexes
    eQTL
    expression Quantatitive Trait Loci
    NHGRI
    National Human Genome Research Institute
    EBI
    European Bioinformatics Insitute
    GWAS
    Genome Wide Association Study
    LD
    linkage disequilibrium.

  • Received December 13, 2018.
  • Revision received June 7, 2019.
  • © 2019 Sousa et al.

Published by The American Society for Biochemistry and Molecular Biology, Inc.

Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.

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Multi-omics Characterization of Interaction-mediated Control of Human Protein Abundance levels
Abel Sousa, Emanuel Gonçalves, Bogdan Mirauta, David Ochoa, Oliver Stegle, Pedro Beltrao
Molecular & Cellular Proteomics August 9, 2019, First published on June 25, 2019, 18 (8 suppl 1) S114-S125; DOI: 10.1074/mcp.RA118.001280

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Multi-omics Characterization of Interaction-mediated Control of Human Protein Abundance levels
Abel Sousa, Emanuel Gonçalves, Bogdan Mirauta, David Ochoa, Oliver Stegle, Pedro Beltrao
Molecular & Cellular Proteomics August 9, 2019, First published on June 25, 2019, 18 (8 suppl 1) S114-S125; DOI: 10.1074/mcp.RA118.001280
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Molecular & Cellular Proteomics: 18 (8 suppl 1)
Molecular & Cellular Proteomics
Vol. 18, Issue 8 suppl 1
9 Aug 2019
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