Graphical Abstract
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.
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.
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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.