Cited by 507Advanced Proteomics Techniques and ApplicationsMass Spectrometry Techniques and ApplicationsMetabolomics and Mass Spectrometry Studies

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Top Down proteomics: Facts and perspectives

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Catherman, Adam D., Skinner, Owen S., Kelleher, Neil L.·2014·Biochemical and Biophysical Research Communications

DOI 10.1016/j.bbrc.2014.02.041PMC PMC4103433

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Abstract

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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Background
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Background
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“However, recent advances in top-down proteomic techniques, involving both intact protein mass measurements and fragmentation of these ions within the mass spectrometer, have enabled such analyses [45].”
BackgroundInfluential
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Method
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Method
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“Continuously improving possibilities of mass spectrometry (MS)-based fragmentation techniques, such as collision induced dissociation (CID) and electron-capture dissociation (ECD),(6) enormously facilitated direct amino acid sequence determination of intact proteins by so-called ‘‘top-down’’ protein sequencing.(7) The…”
Background
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BackgroundSelf-citation
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Edwards, A. N., & Hsu, K. (2024) · Analytica Chimica Acta · doi:10.1016/j.aca.2024.343551 · Cited by 11
Small-Scale Serial Size Exclusion Chromatography (s3SEC) for High Sensitivity Top-Down Proteomics of Large Proteoforms
Rogers, H. T., Melby, J. A., Ehlers, L. E., Fischer, M. S., Larson, E. J., Gao, Z., Rossler, K. J., Wang, D., Alpert, A. J., & Ge, Y. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05733 · Cited by 7
Identification of Alternative Splice Variants Using Unique Tryptic Peptide Sequences for Database Searches
Tran, T. T., Bollineni, R. C., Strozynski, M., Koehler, C. J., & Thiede, B. (2017) · Journal of Proteome Research · doi:10.1021/acs.jproteome.7b00126 · Cited by 7
Selected Reaction Monitoring Mass Spectrometry (SRM-MS) in Proteomics: A Comprehensive View
Hossain, M. (2020) · Selected Reaction Monitoring Mass Spectrometry (SRM-MS) in Proteomics · doi:10.1007/978-3-030-53433-2 · Cited by 8
Top‐down analysis of novel synthetic branched proteins
Gomes, F., Lemma, B., Abeykoon, D., Chen, D., Wang, Y., Fushman, D., & Fenselau, C. (2019) · Journal of Mass Spectrometry · doi:10.1002/jms.4303 · Cited by 7
Mass spectrometry-based proteomics in forensic investigations: a focused review of LC-MS applications
Athira Raj, T., Aravind, G. B., Arun, M., & Aneesh, E. M. (2025) · Egyptian Journal of Forensic Sciences · doi:10.1186/s41935-025-00484-8 · Cited by 7
“This strategy is typically implemfented using advanced instrumentation such as Orbitrap MS or Fourier transform ion cyclotron resonance (FT-ICR) MS, which provide the resolving power necessary for accurate proteoform identification and quantification in complex mixtures [Catherman et al. 2014].”
Exploring snake venoms beyond the primary sequence: From proteoforms to protein-protein interactions
Wang, C. R., McFarlane, L. O., & Pukala, T. L. (2024) · Toxicon · doi:10.1016/j.toxicon.2024.107841 · Cited by 9
A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement
D’Ippolito, R. A., Rabara, D., Blanco, M. A., Alberico, E. O., Drew, M. R., Ramakrishnan, N., Sontan, D., Widmeyer, S. R. T., Scheidemantle, G. M., Messing, S. A. J., et al. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05626 · Cited by 10
Technological development of multidimensional liquid chromatography-mass spectrometry in proteome research
Yu, H., Tai, Q., Yang, C., Gao, M., & Zhang, X. (2023) · Journal of Chromatography A · doi:10.1016/j.chroma.2023.464048 · Cited by 8
Monitoring oxidation in recombinant monoclonal antibodies at subunit level through two-dimensional liquid chromatography coupled with mass spectrometry
Sarin, D., Kumar, S., & Rathore, A. S. (2023) · Journal of Chromatography Open · doi:10.1016/j.jcoa.2023.100086 · Cited by 8
Investigation of Product Ions Generated by 193 nm Ultraviolet Photodissociation of Peptides and Proteins Containing Disulfide Bonds
Macias, L. A., & Brodbelt, J. S. (2022) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.2c00124 · Cited by 9
Improving the Center Section Sequence Coverage of Large Proteins Using Stepped-Fragment Ion Protection Ultraviolet Photodissociation
Dunham, S. D., Sanders, J. D., Holden, D. D., & Brodbelt, J. S. (2022) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.1c00296 · Cited by 10
Top-down proteomic identification of plasmid and host proteins produced by pathogenic Escherichia coli using MALDI-TOF-TOF tandem mass spectrometry
Fagerquist, C. K., & Dodd, C. E. (2021) · PLoS ONE · doi:10.1371/journal.pone.0260650 · Cited by 7
“Top-down proteomic analysis is the determination of the mass, sequence, and post-translational modifications (PTMs) of a mature intact protein without prior proteolytic digestion [6].”
BackgroundMethod
Electrospray Ionization-Mass Spectrometry of Synthetic Polymers Functionalized with Carboxylic Acid End-Groups
Nitsche, T., Sheil, M. M., Blinco, J. P., Barner‐Kowollik, C., & Blanksby, S. J. (2021) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.1c00085 · Cited by 7
Quantitative LC-MS proteoform profiling of intact wheat glutenin subunits
Bacala, R., Fu, B. X., Perreault, H., & Hatcher, D. W. (2020) · Journal of Cereal Science · doi:10.1016/j.jcs.2020.102963 · Cited by 7
A Markov Chain Monte Carlo Method for Estimating the Statistical Significance of Proteoform Identifications by Top-Down Mass Spectrometry
Kou, Q., Wang, Z., Lubeckyj, R. A., Wu, S., Sun, L., & Liu, X. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00562 · Cited by 8
Proteomic approaches for cancer epigenetics research
Marchione, D. M., Garcia, B. A., & Wojcik, J. B. (2018) · Expert Review of Proteomics · doi:10.1080/14789450.2019.1550363 · Cited by 7
“Like middle-down, top-down proteomics remains technically challenging, but it is constantly becoming more accessible [25].”
Background
Replacing H + by Na + or K + in phosphopeptide anions and cations prevents electron capture dissociation
Schneeberger, E., & Breuker, K. (2018) · Chemical Science · doi:10.1039/c8sc02470g · Cited by 10
Proteogenomics approaches for studying cancer biology and their potential in the identification of acute myeloid leukemia biomarkers
Hernandez-Valladares, M., Vaudel, M., Selheim, F., Berven, F. S., & Bruserud, Ø. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2017.1352474 · Cited by 12
“represents a promising solution to the inference challenges of peptide-based proteomics [81,82].”
Background
Global Proteomics of Extremophilic Fungi: Mission Accomplished?
Tesei, D., Sterflinger, K., & Marzban, G. (2019) · Fungi in Extreme Environments: Ecological Role and Biotechnological Significance · doi:10.1007/978-3-030-19030-9_12 · Cited by 7
Proteomics: Tools of the Trade
Bose, U., Wijffels, G. L., Howitt, C. A., & Colgrave, M. L. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12298-0_1 · Cited by 18
Cysteine-Directed Isobaric Labeling Combined with GeLC-FAIMS-MS for Quantitative Top-Down Proteomics
Matzanke, T., Kaulich, P. T., Jeong, K., Takemori, A., Takemori, N., Kohlbacher, O., & Tholey, A. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.4c00835 · Cited by 8
Pericyte-Specific Secretome Profiling in Hypoxia Using TurboID in a Multicellular in Vitro Spheroid Model
Enström, A., Carlsson, R., Buizza, C., Lewi, M., & Paul, G. (2024) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2024.100782 · Cited by 7
“Although LC-MS/MS achieves high throughput, accuracy, and reproducibility in proteomic analysis, its limitation in sensitivity is still an issue when characterizing proteomic data (36).”
A combined top-down and bottom-up LC-HRMS/MS method for the quantification of human growth hormone in plasma and serum
Krombholz, S., Thomas, A., Delahaut, P., Bidlingmaier, M., Schilbach, K., Miller, G. D., & Thevis, M. (2023) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2023.101560 · Cited by 7
Microprobe-Capture In-Emitter Elution: An Affinity Capture Technique to Directly Couple a Label-Free Optical Sensing Technology with Mass Spectrometry for Protein Analysis.
Luo, R.-B. Y., & Yang, S. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c04727 · Cited by 6
Progress in Top-Down LC-MS Analysis of Antibodies: Review
You, J., & Park, H.-M. (2023) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-023-0011-x · Cited by 7
“Conventional CID and HCD may cause the lose of PTMs as mentioned above, so an alternative fragmentation method, ultraviolet photodissociation (UVPD) was developed to minimize the loss of labile PTMs, including ECD and ETD [64].”
BackgroundInfluential
The lysosomal endopeptidases Cathepsin D and L are selective and effective proteases for the middle‐down characterization of antibodies
Čaval, T., Hecht, E. S., Tang, W. H., Uy‐Gomez, M., Nichols, A. C., Kil, Y. J., Sandoval, W. N., Bern, M. W., & Heck, A. J. R. (2021) · FEBS Journal · doi:10.1111/febs.15813 · Cited by 6
Proteoform characterization based on top-down mass spectrometry
Zhong, J., Sun, Y., Xie, M., Peng, W., Zhang, C., Wu, F., & Wang, J. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa015 · Cited by 11
Mass spectrometry: Raw protein from the top down.
Breuker, K. (2018) · Nature Chemistry · doi:10.1038/nchem.2936 · Cited by 6
Characterization Methods: Physical and Chemical Characterization Techniques
Borgos, S. E. (2016) · Wiley eBooks · doi:10.1002/9783527800681.ch7 · Cited by 1
Comparative studies of peak intensities and chromatographic separation of proteolytic digests, PTMs, and intact proteins obtained by nanoLC-ESI MS analysis at room and elevated temperatures
Moskovets, E. V., & Ivanov, A. R. (2016) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-016-9386-2 · Cited by 5
Metagenomic Analysis of Low-Temperature Environments
Aliyu, H., Maayer, P. D., Sjöling, S., & Cowan, D. A. (2017) · Springer eBooks · doi:10.1007/978-3-319-57057-0_16 · Cited by 10
Nano-Liquid Chromatographic Separations
Fanali, C., Asensio‐Ramos, M., D’Orazio, G., Hernández‐Borges, J., Rocco, A., & Fanali, S. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-811732-3.00009-1 · Cited by 7
Cross-Linking and Covalent Labeling Mass Spectrometry Reveal Proteoform-Driven Conformational Changes in Alpha Synuclein
Dollar, A. N., & Webb, I. (2026) · Analytical Chemistry · doi:10.1021/acs.analchem.5c05078 · Cited by 6
Tree-based quantification infers proteoform regulation in bottom-up proteomics dataPreprint
Ammar, C., Thielert, M., Weiss, C. A. M., Rodriguez, E. H., Strauss, M. T., Rosenberger, F. A., Zeng, W., & Mann, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.06.641844 · Cited by 10
“Top-down proteomics 19 , which analyzes intact proteins, oXers the most direct approach to proteoform resolution, but faces technical limitations in protein separation and large ion analysis.”
The State of the Art in Transcriptomics and Proteomics of Clinically Relevant Sporothrix Species
Procópio‐Azevedo, A. C., Almeida, M. D. A., Almeida-Paes, R., Zancopé-Oliveira, R., Gutierrez-Galhardo, M. C., de Macedo, P. M., Novaes, E., Bailão, A., Soares, C. M. D. A., & Freitas, D. F. (2023) · Journal of Fungi · doi:10.3390/jof9080790 · Cited by 5
Cell-Type-Specific Neuroproteomics of Synapses
Yim, Y. Y., & Nestler, E. J. (2023) · Biomolecules · doi:10.3390/biom13060998 · Cited by 7
“This ap‐ p oach allows for 100% sequence coverage and complete characterization of proteomes, including genetic variation, alte native splicing, nd post‐translational modification [132].”
Method
Revealing Corynebacterium glutamicum proteoforms through top-down proteomics
Melo, R. M., de Souza, J. M. F., Williams, T. C. R., Fontes, W., de Sousa, M. V., Ricart, C. A. O., & do Vale, L. H. F. (2023) · Scientific Reports · doi:10.1038/s41598-023-29857-6 · Cited by 6
Application of Proteomics in Apical Periodontitis
Hussein, H., & Kishen, A. (2022) · Frontiers in Dental Medicine · doi:10.3389/fdmed.2022.814603 · Cited by 6
“In top-down technique, the intact protein is introduced into the mass spectrometer to measure its intact and fragment ions masses (52).”
Method

Authors: Catherman, A. D., Skinner, O. S., & Kelleher, N. L.
Affiliations: Northwestern University (US)
Corresponding author: Kelleher, Neil L.
ORCID: Skinner, Owen S.
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)
DOI: 10.1016/j.bbrc.2014.02.041
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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