Progress in Top-Down Proteomics and the Analysis of Proteoforms

Toby, Timothy K.; Fornelli, Luca; Kelleher, Neil L.

doi:10.1146/annurev-anchem-071015-041550

Cited by 576Advanced Proteomics Techniques and ApplicationsMass Spectrometry Techniques and ApplicationsMetabolomics and Mass Spectrometry Studies

Progress in Top-Down Proteomics and the Analysis of Proteoforms

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Toby, Timothy K., Fornelli, Luca, Kelleher, Neil L.·2016·Annual Review of Analytical Chemistry

DOI 10.1146/annurev-anchem-071015-041550PMC PMC5373801

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Abstract

From a molecular perspective, enactors of function in biology are intact proteins that can be variably modified at the genetic, transcriptional, or post-translational level. Over the past 30 years, mass spectrometry (MS) has become a powerful method for the analysis of proteomes. Prevailing bottom-up proteomics operates at the level of the peptide, leading to issues with protein inference, connectivity, and incomplete sequence/modification information. Top-down proteomics (TDP), alternatively, applies MS at the proteoform level to analyze intact proteins with diverse sources of intramolecular complexity preserved during analysis. Fortunately, advances in prefractionation workflows, MS instrumentation, and dissociation methods for whole-protein ions have helped TDP emerge as an accessible and potentially disruptive modality with increasingly translational value. In this review, we discuss technical and conceptual advances in TDP, along with the growing power of proteoform-resolved measurements in clinical and translational research.

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Peptide-to-protein inference in bottom-up proteomics causes loss of proteoform information due to shared homologous regions and low sequence coverage.
“However, the ‘peptide-to-protein inference’ problem in bottom-up proteomics leads to a loss in proteoform information because of many homologous sequence regions are shared between different protein forms and the generally low protein sequence coverage is observed [13,14].”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [13]
PTM patterns can provide insight into potentially significant biological processes.
“PTM patterns can provide insight into potentially significant biological processes14,16,17”
From Recent trends of capillary electrophoresis‐mass spectrometry in proteomics research (2019) · cites this paper as [14]
Bottom-up approaches are high-throughput, but critical information about PTMs and subunit protein assemblies is generally lost after proteolysis.
“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 [14]
PTM patterns can often be lost after the protein digestion used in bottom-up approaches.
“but can often be lost after the protein digestion14,18 used in bottom-up approaches”
From Recent trends of capillary electrophoresis‐mass spectrometry in proteomics research (2019) · cites this paper as [14]
Peptide-based methods may limit understanding of the intricate control of diverse biological activities by PTMs.
“Consequently, peptide-based methods may limit our understanding of the intricate and nuanced control of diverse biological activities by PTMs14.”
From Recent trends of capillary electrophoresis‐mass spectrometry in proteomics research (2019) · cites this paper as [14]

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Research works printed but not linked: 2

[3]Nesvizhskii A Aebersold R 2005 Interpretation of shotgun proteomic data: the protein inference problem Mol Cell Proteom 4 1419 40 16009968
[4]Gross JH 2004 Mass Spectrometry: A Textbook New York Springer

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Authors: Toby, T. K., Fornelli, L., & Kelleher, N. L.
Affiliations: Northwestern University (US)
Corresponding author: Kelleher, Neil L.
ORCID: Toby, Timothy K.
Fornelli, Luca
Kelleher, Neil L.
Venue: Annual Review of Analytical Chemistry
Publisher: Annual Reviews
Published: 2016-06-12
Volume: 9
Issue: 1
Pages: 499-519
ISSN: 1936-1327 (ISSN-L)
1936-1335
DOI: 10.1146/annurev-anchem-071015-041550
PMC: PMC5373801
OpenAlex: W2429591244
Cited by: 576
References: 110
Citations by year: 2026: 39 · 2025: 42 · 2024: 36 · 2023: 53 · 2022: 61 · 2021: 71 · 2020: 68 · 2019: 78 · 2018: 63 · 2017: 52 · 2016: 12 · 2015: 1
FWCI: 7.01
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Annual Review of Analytical Chemistry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Science Foundation
University of Wisconsin-Madison
Northwestern University
University of Pittsburgh
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
National Institutes of Health
National Cancer Institute (P30CA060553)
National Institute of General Medical Sciences (P41GM108569, R01GM067193, T32GM105538)
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, proteoforms, protein modification, post-translational modification, prefractionation, protein dissociation, protein inference, clinical proteomics, translational research
MeSH terms: Animals, Humans, Proteins, Mass Spectrometry, Proteomics

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Progress in Top-Down Proteomics and the Analysis of Proteoforms

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