Abstract
The ability of living systems to adapt to changing conditions originates from their capacity to change their molecular constitution. This is achieved by multiple mechanisms that modulate the quantitative composition and the diversity of the molecular inventory. Molecular diversification is particularly pronounced on the proteome level, at which multiple proteoforms derived from the same gene can in turn combinatorially form different protein complexes, thus expanding the repertoire of functional modules in the cell. The study of molecular and modular diversity and their involvement in responses to changing conditions has only recently become possible through the development of new ‘omics’-based screening technologies. This Review explores our current knowledge of the mechanisms regulating functional diversification along the axis of gene expression, with a focus on the proteome and interactome. We explore the interdependence between different molecular levels and how this contributes to functional diversity. Finally, we highlight several recent techniques for studying molecular diversity, with specific focus on mass spectrometry-based analysis of the proteome and its organization into functional modules, and examine future directions for this rapidly growing field.
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Change history
17 April 2020
A Correction to this paper has been published: https://doi.org/10.1038/s41580-020-0249-5
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Acknowledgements
The authors thank all members of the Aebersold laboratory who provided input to the content and presentation of the Review. The authors further thank B. Collins, L. Sieverling, J. Čuklina, C. Dörig, U. Kutay and M. Claassen for reading and providing feedback on different parts of the Review. R.A. acknowledges funding support from the SystemsX.ch projects PhosphoNetX PPM and TbX, as well as from the European Research Council (ERC-20140AdG 670821). I.B. acknowledges funding support from the Swiss National Science Foundation (31003A_166435).
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I.B. researched data for the review. I.B. and R.A. wrote and edited the manuscript before submission.
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Nature Reviews Molecular Cell Biology thanks Ivan Marazzi and the other, anonymous, reviewers for their contribution to the peer review of this work.
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Related links
Complex Portal: https://www.ebi.ac.uk/complexportal/home
CORUM: https://mips.helmholtz-muenchen.de/corum/
GENCODE database: https://www.gencodegenes.org/human/stats.html
Supplementary information
Glossary
- Interactome
-
The whole set of physical interactions between molecules in a cell, here specifically referring to protein–protein interactions.
- Proteoform
-
A protein species with a unique combination of amino acid sequence and post-translational modifications. Multiple alternative proteoforms can originate from the same gene locus.
- Isoforms
-
Alternative mRNA transcripts originating from the same gene locus.
- Epitranscriptome
-
The whole set of biochemical modifications of RNAs in a cell, with the methylation of adenosine being the most prominent modification.
- Alternative polyadenylation
-
Deviations from the standard process of polyadenylation, including the usage of different poly(A) start sites or variable length of the transcript’s 3′ untranslated region.
- Synonymous substitutions
-
DNA base substitutions in an exon of a protein-coding gene that do not cause a change in the translated protein sequence.
- N-degron pathways
-
A set of proteolytic systems that can recognize proteins containing N-degrons, thereby causing the degradation of these proteins (formerly ‘N-end rule pathways’). N-degrons are degradation signals in the amino-terminal region of a protein, which relate its in vivo half-life to the identity of its amino-terminal composition.
- C-degron pathways
-
A set of proteolytic systems that can recognize proteins containing C-degrons, thereby causing the degradation of these proteins. C-degrons are degradation signals in the carboxy-terminal region of a protein, which relate its in vivo half-life to the identity of its carboxy-terminal composition.
- SUMOylation
-
The post-translational modification of a protein by covalently attached small ubiquitin-like modifier (SUMO) proteins.
- Alternative splicing-coupled nonsense-mediated mRNA decay
-
A regulatory mechanism in which alternative splicing events introduce premature termination codons that lead to the downregulation of the transcript through the process of nonsense-mediated mRNA decay.
- Quantitative trait loci
-
DNA loci that correlate with the variation of a quantitative trait in the phenotype.
- Yeast two-hybrid screens
-
(Y2H screens). A strategy to identify protein–protein interactions in which one target protein is fused with a DNA-binding domain and a second target protein is fused with a respective transcriptional activation domain. When co-expressed in yeast, if the two target proteins interact in the nucleus, they initiate the transcription of a reporter gene.
- Co-fractionation coupled to mass spectrometry
-
(CoFrac-MS). A strategy for the global mapping of protein–protein interactions and protein complexes, involving the native extraction and subsequent separation of protein complexes according to their physicochemical properties, followed by mass spectrometry analysis.
- False discovery rates
-
A metric used for the control of the error rate in experiments affected by the multiple testing problem.
- Graph partitioning
-
The process of dividing a graph (for example, a protein–protein interaction network) into smaller connected subnetworks.
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Bludau, I., Aebersold, R. Proteomic and interactomic insights into the molecular basis of cell functional diversity. Nat Rev Mol Cell Biol 21, 327–340 (2020). https://doi.org/10.1038/s41580-020-0231-2
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DOI: https://doi.org/10.1038/s41580-020-0231-2
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