Key Points
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Post-translational modifications (PTMs) affect protein conformation and interactions and can mediate the sequestration of proteins to cellular compartments and organelles.
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The integration of molecular-cell-biology, protein-mass-spectrometry and bioinformatics technologies facilitates the study of protein PTMs.
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Mass spectrometry identifies PTMs by looking for distinct mass increments or diagnostic PTM-specific signals that are generated by the tandem-mass-spectrometry analysis of peptides and proteins.
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Modification-specific proteomics takes advantage of organelle purification and PTM-specific affinity-enrichment methods, multidimensional peptide-separation methods and tandem mass spectrometry to achieve high sensitivity and selectivity for the determination of PTMs.
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The quantitative analysis of PTMs is possible. This can be achieved by using two-dimensional gel-based methods and imaging or by using liquid-chromatography–mass-spectrometry together with peptide-intensity-profiling or stable-isotope-labelling approaches.
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Functional phosphoproteomics studies are delineating cellular signal-transduction cascades and revealing new regulatory mechanisms in microbes, plants and mammals.
Abstract
Post-translational modifications define the functional and structural plasticity of proteins in archaea, prokaryotes and eukaryotes. Multi-site protein modification modulates protein activity and macromolecular interactions and is involved in a range of fundamental molecular processes. Combining state-of-the-art technologies in molecular cell biology, protein mass spectrometry and bioinformatics, it is now feasible to discover and study the structural and functional roles of distinct protein post-translational modifications.
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Acknowledgements
I thank my colleagues in the Protein Research Group, as well as numerous colleagues in the world of proteomics, for many interesting and stimulating scientific discussions. I am grateful to M. B. Trelle for his assistance in preparing the figures. This manuscript is dedicated to the memory of my late father, Alex B. Jensen (1940–2005).
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FURTHER INFORMATION
Center for Biological Sequence Analysis Prediction Servers (Technical University of Denmark)
Human Protein Reference Database (HPRD)
HUPO Proteomics Standards Initiative
PhosphoELM (a database of S/T/Y phosphorylation sites)
Protein Research Group, University of Southern Denmark
Glossary
- ChIP-on-chip
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A chromatin immunoprecipitation (ChIP) experiment that uses protein–DNA crosslinking, specific antibodies and cDNA microarrays ('chips') for large-scale studies of DNA-binding proteins, including the analysis of post-translational modifications.
- Microfluidics
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Nanolitre-flow chromatographic systems for protein and peptide separations prior to mass-spectrometry analysis.
- Electrospray ionization
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A 'soft' ionization method for mass spectrometry that generates gas-phase ions from peptide and protein solutions through the vapourization of liquid in an electric field.
- Matrix-assisted laser desorption/ionization
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A 'soft' ionization technique for mass spectrometry that produces gas-phase ions through the pulsed, ultraviolet laser irradiation of crystalline deposits of peptides and proteins.
- TiO2 columns
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Titanium dioxide interacts with phosphate groups by a chelation mechanism. These columns are therefore useful for the selective and specific enrichment of phosphopeptides.
- β-elimination reaction
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The alkaline-induced elimination of phosphoric acid from phosphoserine and phosphothreonine residues or of O-linked sugars from O-glycosylated residues in peptides.
- Michael addition reaction
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The addition of a functional chemical moiety to a residue that was post-translationally modified but that has undergone a β-elimination reaction. Affinity tags or mass tags can be added to allow the specific recovery or detection of post-translationally modified peptides.
- Phosphoramidate chemistry
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A method for the selective capture of converted post-translationally modified peptides, with the aim of identifying the modified protein and the site of the modification.
- Chromatographic stationary phases
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The column resins that are used for the chromatographic separation of molecules — for example, a reversed-phase resin or a strong-cation-exchange resin.
- Cell-signalling cassettes
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Multiprotein modules that are involved in signal-transduction processes and that rapidly propagate stimuli from cell-surface receptors to the cytosol or the nucleus.
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Jensen, O. Interpreting the protein language using proteomics. Nat Rev Mol Cell Biol 7, 391–403 (2006). https://doi.org/10.1038/nrm1939
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DOI: https://doi.org/10.1038/nrm1939
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