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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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Halim, A., Carlsson, M. C., Madsen, C. B., Brand, S., Møller, S. R., Olsen, C. E., Vakhrushev, S. Y., Brimnes, J., Würtzen, P. A., Ipsen, H., et al. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.042614 · Cited by 38
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Liquid chromatography above 20,000 PSI
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“Future top-down proteomic analyses [49,50] would be necessary in order to specifically address this question.”
BackgroundProtein species as diagnostic markers
Steffen, P., Kwiatkowski, M., Robertson, W. D., Zarrine‐Afsar, A., Deterra, D., Richter, V., & Schlüter, H. (2015) · Journal of Proteomics · doi:10.1016/j.jprot.2015.12.015 · Cited by 36
Improved Identification of Proteoforms in Top-Down Proteomics Using FAIMS with Internal CV Stepping
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“ETD/ ECD fragmentations can be used in two ways: top-down (where the intact protein is fragmented and its regional behavior studied) and bottom up (Pan et al., 2009; Catherman et al., 2014; Karch et al., 2018).”
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McCabe, J. W., Mallis, C. S., Kocurek, K. I., Poltash, M. L., Shirzadeh, M., Hebert, M. J., Fan, L., Walker, T. E., Zheng, X., Jiang, T., et al. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c01285 · Cited by 37
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“However, top-down-proteomics faces other challenges, such as limited solubility, insignificant ionization and complex fragmentation of proteins [37].”
BackgroundChallenges and developments in protein identification using mass spectrometry
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“Several IMS-TOF instruments have been available for years, but the real benefits of these in top-down or bottom-up proteomics were recognized just recently and accepted by the proteomics community [78].”
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Николаевна, С. Г., Gorbach, D., Lukasheva, E., Mavropolo-Stolyarenko, G., Bilova, T. E., Soboleva, A., Tsarev, A. A., Romanovskaya, E. V., Podolskaya, E. P., Zhukov, V. A., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239162 · Cited by 41
“In the first case, ions of individual proteins with molecular weight below 25 kDa are measured directly, including fragmentation and MS/MS acquisition of protein fragment ions [58,59], whereas the bottom-up strategy employs proteolytic digestion of protein mixtures prior to MS and MS/MS analysis of the resulting prote…”
MethodTop-Down Analysis of Proteins in Low Charge States
Bashyal, A., Sanders, J. D., Holden, D. D., & Brodbelt, J. S. (2019) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-019-02146-1 · Cited by 37
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“Native top-down proteomics (nTDP) integrates nMS with top-down proteomics (TDP) (Catherman et al. 2014; Toby et al. 2016; Chen et al. 2018; Melby et al. 2021), which enables structural characterization of protein complexes together with proteo-form sequencing to locate non-covalent ligand binding…”
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“Here, we analyze complex mass spectral datasets obtained during top-down protein fragmentation (fragmentation of a single intact protein) [15].”
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“These include intact proteins with a higher priority into analyses than fragmented ones (Catherman et al., 2014).”
Fungal Coculture: Unlocking the Potential for Efficient Bioconversion of Lignocellulosic Biomass
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“the fragmentation of the intact proteins during analysis, or the analysis of the intact proteins using “native”mass spectrometry [7].”
MethodSavaryn, J. P., Toby, T. K., Catherman, A. D., Fellers, R. T., LeDuc, R. D., Thomas, P. M., Friedewald, J. J., Salomon, D. R., Abecassis, M. M., & Kelleher, N. L. (2016) · PROTEOMICS · doi:10.1002/pmic.201600008 · Cited by 23
“Top down proteomics measures proteins in their intact state affording information on exact molecular weight, protein identity, and the type, location, and relative abundance of PTMs [10].”
BackgroundSelf-citationMonitoring therapeutic monoclonal antibodies in brain tumor
Ait‐Belkacem, R., Bérenguer, C., Villard, C., Ouafik, L., Figarella-Branger, D., Beck, A., Chinot, O., & Lafitte, D. (2014) · mAbs · doi:10.4161/mabs.34405 · Cited by 23
“This “top-down” approach has been previously used for extensive characterization of post-translational modifications.(36,37) In-source decay (ISD) is the top-down approach occurring during the matrix-assisted laser desorption/ionization (MALDI) steps.”
MethodGreening, D. W., Kapp, E. A., & Simpson, R. J. (2017) · The Enzymes · doi:10.1016/bs.enz.2017.08.003 · Cited by 23
From flesh to bones: Multi‐omics approaches in forensic science
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Impact of Internal Fragments on Top-Down Analysis of Intact Proteins by 193 nm UVPD
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Characterization of Contractile Proteins from Skeletal Muscle Using Gel-Based Top-Down Proteomics
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Portevin, D., Pflüger, V., Otieno, P., Brunisholz, R., Vogel, G., & Daubenberger, C. (2015) · BMC Biotechnology · doi:10.1186/s12896-015-0140-1 · Cited by 26
“Accordingly, within a single spectrum whole-cell mass spectrometry would capture generic activation patterns as well as activation event specific from distinct signalling pathways which remain to be elucidated using for instance, top-down proteomic approaches [39].”
BackgroundSchweitzer, M. H., Schroeter, E. R., & Goshe, M. B. (2014) · Analytical Chemistry · doi:10.1021/ac500803w · Cited by 28
Qualitative and Quantitative Mass Spectrometry in Salivary Metabolomics and Proteomics
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“On the other hand, in the top-down approach, the protein is extracted from cell lysates, separated by liquid chromatography or gel electrophoresis, and then analysed in a mass spectrometer [100,101].”
Methodvon Reumont, B. M., Anderluh, G., Antunes, A., Ayvazyan, N. M., Beis, D., Çalışkan, F., Crnković, A., Damm, M., Dutertre, S., Ellgaard, L., et al. (2022) · GigaScience · doi:10.1093/gigascience/giac048 · Cited by 131
“Nonetheless,for high molecular mass toxin proteins ( > 30 kDa), current top-down analyses run into technical limits [87, 97].”
The proteome and its dynamics: A missing piece for integrative multi-omics in schizophrenia
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“Importantly, they enable us to analyze not only the abundance of proteins, but also their functional properties, their subcellular locale, PTMs and PPIs.”
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Principles of phosphoproteomics and applications in cancer research
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Preclinical and Clinical Applications of Metabolomics and Proteomics in Glioblastoma Research
Ahmed, M., Semreen, A. M., El‐Huneidi, W., Bustanji, Y. K., Abu‐Gharbieh, E., Alqudah, M. A. Y., Alhusban, A., Shara, M., Abuhelwa, A. Y., Soares, N. C., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010348 · Cited by 25
“Individual post-translational alterations may be identified and quantified using this technique, owing to the lack of the enzymatic digestion step in top-down proteomics [40].”
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“Top–down proteomics introduces the intact proteins into MS for the analysis of both intact proteins and their fragments, which allows integrated sequence coverage and full characterization of proteoforms but presents defects in sensitivity and throughput [63, 64].”
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Rogawski, R., Rogel, A., Bloch, I., Gal, M., Horovitz, A., London, N., & Sharon, M. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202104947 · Cited by 18
Direct identification of bacterial and human proteins from infected wounds in living 3D skin models
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Advances in Proteomics Allow Insights Into Neuronal Proteomes
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Enhancing Open Modification Searches via a Combined Approach Facilitated by Ursgal
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“The identification of intact proteoforms in top-down proteomics provides unique opportunities, such as insights into relationships between PTMs on the same protein 17 .”
BackgroundProteomics in idiopathic pulmonary fibrosis: the quest for biomarkers
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“In contrast to the conventional bottom-up proteomics approach wherein proteins are digested into peptides prior to mass spectrometry (MS) analysis, intact proteins are analyzed in the top-down proteomics workflow, which provides a “bird’s eye” view of all proteoforms [22] (a term encompassing all protein variants of t…”
BackgroundMining seed proteome: from protein dynamics to modification profiles
Frolov, A., Мамонтова, Т. В., Ihling, C. H., Lukasheva, E., Bankin, M., Chantseva, V. V., Vikhnina, M., Soboleva, A., Shumilina, J., Mavropolo-Stolyarenko, G., et al. (2018) · Biological Communications · doi:10.21638/spbu03.2018.106 · Cited by 381
Modulation of Protein Fragmentation Through Carbamylation of Primary Amines
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“length protein) have been developed that enable injection of proteins into the MS and allow amino acid sequencing and observation of PTM [5, 6].”
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CE-MS for the analysis of intact proteins
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Spacer Fidelity Assessments of Guide RNA by Top-Down Mass Spectrometry
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“Proteoforms of low abundance can be overlooked [29] and some factors such as protein solubility, proteome complexity, and proteoform function should be considered before beginning the experiment [30].”
BackgroundShort open reading frame genes in innate immunity: from discovery to characterization
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Lights and Shadows of TORCH Infection Proteomics
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“The term “proteomics” is defined as the science that studies the proteome, which consists of the total protein content of a cell, tissue or organism, including PTMs and protein–protein interactions [22].”
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“In the last two decades, top-down mass spectrometry (MS) has become an established technique for the analysis of protein sequence and the detailed characterisation of posttranslational and chemical protein modifications[1, 2].”
Protein Analysis by Shotgun Proteomics
Gao, Y., & Yates, J. R. (2019) · Wiley eBooks · doi:10.1002/9781118970195.ch1 · Cited by 21
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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