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Top Down proteomics: Facts and perspectives
Open accessAbstract
The rise of the "Top Down" method in the field of mass spectrometry-based proteomics has ushered in a new age of promise and challenge for the characterization and identification of proteins. Injecting intact proteins into the mass spectrometer allows for better characterization of post-translational modifications and avoids several of the serious "inference" problems associated with peptide-based proteomics. However, successful implementation of a Top Down approach to endogenous or other biologically relevant samples often requires the use of one or more forms of separation prior to mass spectrometric analysis, which have only begun to mature for whole protein MS. Recent advances in instrumentation have been used in conjunction with new ion fragmentation using photons and electrons that allow for better (and often complete) protein characterization on cases simply not tractable even just a few years ago. Finally, the use of native electrospray mass spectrometry has shown great promise for the identification and characterization of whole protein complexes in the 100 kDa to 1 MDa regime, with prospects for complete compositional analysis for endogenous protein assemblies a viable goal over the coming few years.
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“This approach is well-known for its high-throughput performance; however, critical information about PTMs and subunit protein assemblies (via non-covalent interactions) is generally lost after proteolysis14,31.”
From Recent trends of capillary electrophoresis‐mass spectrometry in proteomics research (2019) · cites this paper as [31]
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Soboleva, A., Schmidt, R., Vikhnina, M., Grishina, T., & Frolov, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122677 · Cited by 47
Accelerating the Field of Epigenetic Histone Modification Through Mass Spectrometry–Based Approaches
Lu, C., Coradin, M., Porter, E. G. P., & Garcia, B. A. (2020) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r120.002257 · Cited by 71
“in the top–down field, have described the history and fundamental concepts of top–down proteomics and discuss recent technical and conceptual advances (35, 36).”
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Abiraami, T. V., Singh, S., & Nain, L. (2019) · Reviews in Environmental Science and Bio/Technology · doi:10.1007/s11157-019-09519-8 · Cited by 63
Sanders, J. D., Mullen, C., Watts, E., Holden, D. D., Syka, J. E. P., Schwartz, J. C., & Brodbelt, J. S. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b04026 · Cited by 55
It is time for top-down venomics
Melani, R. D., Nogueira, F. C. S., & Domont, G. B. (2017) · The Journal of venomous animals and toxins including tropical diseases · doi:10.1186/s40409-017-0135-6 · Cited by 49
“of charge states increasing signal-to-noise ratio because of lower number of channels to split ion intensity [16].”
BackgroundMethodProfiling microbial lignocellulose degradation and utilization by emergent omics technologies
Rosnow, J. J., Anderson, L. N., Nair, R., Baker, E. S., & Wright, A. (2016) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2016.1209158 · Cited by 51
“[51] Additionally, the ability to identify peptide fragments has improved greatly due to the depth of genome sequence and the bioinformatics tools available.”
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The effects of nonignorable missing data on label-free mass spectrometry proteomics experiments
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Recent Advances in Mass Spectrometry-Based Structural Elucidation Techniques
Ma, X. (2022) · Molecules · doi:10.3390/molecules27196466 · Cited by 57
Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches
Jafari, A., Babajani, A., & Rezaei–Tavirani, M. (2021) · Biomarker Insights · doi:10.1177/11772719211013352 · Cited by 48
Welker, M., & van Belkum, A. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02711 · Cited by 50
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“Massbased approaches are well suited in terms of sensitivity and throughput [17].”
Standardization of a protocol for shotgun proteomic analysis of saliva
Ventura, T. M. D. S., Ribeiro, N. R., Dionizio, A., Sabino, I. T., & Buzalaf, M. (2018) · Journal of Applied Oral Science · doi:10.1590/1678-7757-2017-0561 · Cited by 39
Characterization of microbial mixtures by mass spectrometry
Sandrin, T. R., & Demirev, P. A. (2017) · Mass Spectrometry Reviews · doi:10.1002/mas.21534 · Cited by 44
The Ups and Downs of Repeated Cleavage and Internal Fragment Production in Top-Down Proteomics
Lyon, Y. A., Riggs, D. L., Fornelli, L., Compton, P. D., & Julian, R. R. (2017) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-017-1823-8 · Cited by 44
Vehus, T., Ro̷berg-Larsen, H., Waaler, J., Aslaksen, S., Krauss, S., Wilson, S., & Lundanes, E. (2016) · Scientific Reports · doi:10.1038/srep37507 · Cited by 39
Liu, J., Yang, L., Liu, D., Wu, Q., Yu, Y., Huang, X., Li, J., & Liu, S. (2025) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2025.07.006 · Cited by 38
Identification of Splice Variants and Isoforms in Transcriptomics and Proteomics
Su, T., Hollas, M. A. R., Fellers, R. T., & Kelleher, N. L. (2023) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-020722-044021 · Cited by 40
“In contrast, TD proteomics analyzes either denatured or native intact proteins without enzymatic digestion (21).”
BackgroundSelf-citationThuy-Boun, P. S., Wang, A. Y., Crissien-Martinez, A., Xu, J. H., Chatterjee, S., Stupp, G. S., Su, A. I., Coyle, W., & Wolan, D. W. (2022) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2022.100197 · Cited by 44
“), perhaps genomics-agnostic, middle- and top-down proteomics sequencing could be applied (109, 110).”
Mass spectrometry and the cellular surfaceome
Pauwels, J., Fijałkowska, D., Eyckerman, S., & Gevaert, K. (2021) · Mass Spectrometry Reviews · doi:10.1002/mas.21690 · Cited by 48
Mesleh, A. G., Abdulla, S. A., & El‐Agnaf, O. M. A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11010041 · Cited by 41
“Abbreviations ADHD Attention deficit hyperactivity disorder ADOS Autism Diagnostic Observation Schedule AGE Glycation end products ASD Autism spectrum disorder BA10 Brodmann area 10 CARS Childhood Autism Rating Scale CGH Comprehensive genomic hybridization CNV Copy number variant CSF Cerebrospinal fluid CVD Cardiovasc…”
BackgroundCiocan, C. A., Jurj, A. M., Buse, M., Gulei, D., Braicu, C., Ráduly, L., Cojocneanu, R., Pruteanu, L.-L., Iuga, C. A., Coza, O. F., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102576 · Cited by 43
“A frequently used method representative of the top-down strategy is protein ionization by matrix-assisted laser desorption ionization (MALDI) and mass measurement by time-of-flight (TOF) mass analyzer [32].”
MethodFoodomics: A novel approach for food microbiology
Xu, Y. (2017) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2017.05.012 · Cited by 50
Metadata
- Authors
- Catherman, A. D., Skinner, O. S., & Kelleher, N. L.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Kelleher, Neil L.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 445
- Issue
- 4
- Pages
- 683-693
- ISSN
- 0006-291X (ISSN-L)
- PMC
- PMC4103433
- OpenAlex
- W2070948666
- Cited by
- 507
- References
- 143
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 31 · 2023: 37 · 2022: 48 · 2021: 49 · 2020: 49 · 2019: 46 · 2018: 41 · 2017: 59 · 2016: 38 · 2015: 42 · 2014: 14
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM067193)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- top-down proteomics, post-translational modification, protein characterization, protein separation, protein complex identification
- MeSH terms
- Amino Acid Sequence, Animals, Chromatography, Liquid, Electrophoresis, Equipment Design, Humans, Molecular Sequence Data, Proteins, Mass Spectrometry, Proteomics
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