Quantifying Homologous Proteins and Proteoforms
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Abstract
Many proteoforms – arising from alternative splicing, post-translational modifications (PTMs), or paralogous genes – have distinct biological functions, such as histone PTM proteoforms. However, their quantification by existing bottom-up mass–spectrometry (MS) methods is undermined by peptide-specific biases. To avoid these biases, we developed and implemented a first-principles model (HI quant ) for quantifying proteoform stoichiometries. We characterized when MS data allow inferring proteoform stoichiometries by HI quant , derived an algorithm for optimal inference, and demonstrated experimentally high accuracy in quantifying fractional PTM occupancy without using external standards, even in the challenging case of the histone modification code. A HI quant server is implemented at: https://web.northeastern.edu/slavov/2014_HIquant/
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Cites
Mass spectrometry–based proteomics turns quantitative
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How many human proteoforms are there?
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Decoding protein modifications using top-down mass spectrometry
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Plubell, D. L., Käll, L., Webb-Robertson, B.-J., Bramer, L. M., Ives, A., Kelleher, N. L., Smith, L. M., Montine, T. J., Wu, C. C., & MacCoss, M. J. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00894 · Cited by 85 · see citing works
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“This issue is especially hard to deal in a bottom-up approach, where peptides generated due to enzymatic digestion could be shared between multiple proteoforms [111].”
BackgroundMethodInfluential
- Authors
- Malioutov, D., Chen, T., Airoldi, E., Jaffe, J., Budnik, B., & Slavov, N.
- Affiliations
- IBM (United States) (US)
- Northeastern University (US)
- Broad Institute (US)
- Corresponding author
- Slavov, Nikolai
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 18
- Issue
- 1
- Pages
- 162-168
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC6317479
- OpenAlex
- W2736896644
- Cited by
- 21
- References
- 6
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 3
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- arXiv (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- HHS | NIH | National Institute of General Medical Sciences (1DP2OD022522–01)
- 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 › Redox biology and oxidative stress
- Keywords
- homologous proteins, histone modifications, histone H3, bottom-up mass spectrometry, first-principles modeling, inference algorithms, alternative splicing, paralogs, quantitative proteomics
- MeSH terms
- Algorithms, Alkylation, Histones, Protein Processing, Post-Translational, Software, Sequence Homology, Amino Acid, Alternative Splicing, Proteomics, Tandem Mass Spectrometry
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