Proteoforms as the next proteomics currency
Open accessAbstract
Identifying precise molecular forms of proteins can improve our understanding of function
AI snapshot
Written from the paper’s full text.
TL;DR
The article argues that proteomics should shift from measuring peptide proxies to directly identifying and quantifying proteoforms—distinct protein forms generated by sequence variation, splicing, and posttranslational modification. It reviews bottom-up, top-down, and intact-mass/proteoform-family strategies and calls for integrated proteogenomic approaches and a proteoform atlas.
Key findings
- The paper cites evidence that splice variants from a single gene can differ functionally as much as proteins from different genes and can influence complex traits, yet standard bottom-up proteomics digests proteins into peptides and loses direct proteoform identity because one peptide may derive from many forms.
- Top-down proteomics analyzes intact proteins and has advanced for high-mass proteins and complex samples, but still faces limits in sequence coverage and low-abundance detection.
- A yeast proteome-wide approach used intact mass plus lysine-count measurements, comparing experimental masses with a theoretical proteoform database and with one another, to identify proteoforms and assemble them into related “families.”
- Histone studies found far fewer proteoforms than combinatorial possibilities: one deep histone H4 study identified 74, compared with roughly 3 million theoretical possibilities from known site-specific modifications; the paper notes more than 400 known PTMs and says the discrepancy may reflect detection limits or biological restraint.
Methods
- This is a perspective/commentary rather than primary research; it does not generate a new experimental sample or dataset.
- It synthesizes cited literature on bottom-up peptide-based tandem MS, top-down intact-protein tandem MS, and an intact-mass/lysine-count proteoform identification strategy, along with RNA-sequencing-based sample-specific databases and integrated proteogenomic analysis.
- The main analysis is conceptual: it contrasts proteomic paradigms, uses cited examples, and argues for proteoform-level measurement and atlas building.
Limitations
- Stated in the paper: top-down methods have incomplete sequence coverage and difficulty analyzing low-abundance species; current mass spectrometers detect only proteoforms above their detection thresholds; and the total number of natural proteoforms may be impossible to determine because rare transcription/translation errors can create very low-abundance forms.
- Stated in the paper: observed histone proteoform counts are much lower than theoretical combinatorial possibilities, and it remains unclear whether this reflects technological limits or biology using only a subset of possible forms.
- Evident from the text: as a perspective, it offers no new experimental validation or quantitative benchmarks, so its conclusions depend on cited studies and proposed integration strategies.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 16 cited sources checked · 0 supported · 0 flagged
- Premisecitation§ Proteoforms as the next proteomics currency
Splice variants are centrally involved in the modulation of complex traits.
“Li et al. (3) showed that splice variants play a central role in modulating complex traits.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Li YI Science 352 600 2016 27126046 PMC5182069 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
The conventional bottom-up approach to proteomics does not directly identify proteoforms.
“However, the standard paradigm of proteomic analysis, the “bottom-up” strategy pioneered by Eng and Yates some 20 years ago (4), does not directly identify proteoforms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Eng JK McCormack AL Yates JR J. Am. Soc. Mass Spectrom 5 976 1994 24226387 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
Splice variants from one gene can yield proteins whose functional differences are as large as those between proteins from completely different genes.
“Yang et al. (2) recently showed that the functions of proteins produced from splice variants from a given gene—different proteoforms—can be as different as those for proteins encoded by entirely different genes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Yang X Cell 164 805 2016 26871637 PMC4882190 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
Only inferences can be drawn about the actual proteoform or proteoforms from which an identified peptide came.
“However, only inferences can be made as to the actual proteoform or proteoforms from which the identified peptide was derived (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Nesvizhskii AI Aebersold R Mol. Cell. Proteomics 4 1419 2005 16009968 source
Not checked in the free run.
- Interpretationreasoning§ Proteoforms as the next proteomics currency
Because multiple gene products, isoforms, and proteoforms can share a peptide, bottom-up proteomics loses direct information about which proteoforms are present.
“However, as many different gene products, isoforms, and proteoforms can contain the same peptide, direct information about the proteoforms present is lost (see the figure, bottom).”
Quote in the paperSubstantial claim- Rests on an assumption: In bottom-up proteomics, each identified peptide serves as a surrogate for the presence of the protein molecule from which it was derived.
- Premisecitation§ Proteoforms as the next proteomics currency
Histone proteoform analysis by Garcia and coworkers found far fewer histone proteoform variants than the maximal combinatorial possibilities would suggest.
“Garcia and coworkers have pioneered MS methods for histone proteoform analysis, finding much smaller numbers of histone proteoform variants than the maximal number of combinatorial possibilities would suggest (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Yuan Z-F Arnaudo AM Garcia BA Annu. Rev. Analyt. Chem 7 113 2014 PMC4130481 24896311 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
A deep study of histone H4 proteoforms by Coon and co-workers identified only 74.
“Similarly, in a deep study of histone H4 proteoforms by Coon and co-workers, only 74 were identified (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Phanstiel D Proc. Natl. Acad. Sci. U.S.A 105 4093 2008 18326628 PMC2393763 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
A complementary approach identified proteoforms across the yeast proteome using high-accuracy intact mass measurements aided by lysine residue counts.
“A complementary approach reported the proteome-wide identification of proteoforms in yeast, based primarily upon a high-accuracy determination of their intact mass, aided by a corollary measurement of the number of lysine residues in the molecule (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Shortreed MR J. Proteome Res 15 1213 2016 26941048 PMC4917391 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
Comparing measured masses and lysine counts with a theoretical database of possible yeast proteoforms produced proteoform identifications.
“Comparison of the measured masses and lysine counts with a theoretical database of possible yeast proteoforms yielded proteoform identifications.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Shortreed MR J. Proteome Res 15 1213 2016 26941048 PMC4917391 source
Not checked in the free run.
- Premisecitation§ Proteoforms as the next proteomics currency
Comparing experimental masses with one another revealed related proteoforms that differ by common PTMs, yielding additional identifications.
“Further comparisons of all experimental masses with one another revealed related proteoforms differing by common PTMs, yielding more identifications.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Shortreed MR J. Proteome Res 15 1213 2016 26941048 PMC4917391 source
Not checked in the free run.
- Interpretationreasoning§ Proteoforms as the next proteomics currency
Combining proteogenomic data with bottom-up, top-down, and intact mass measurements can provide the comprehensive analysis needed to identify and quantify proteoforms broadly in complex samples.
“Integrating such proteogenomic data with synergistic information obtained from bottom-up (for PTM identification and localization), top-down (for protein identification and PTM localization), and intact mass measurements (for proteoform identification) can provide the comprehensive analysis needed to broadly identify and quantify proteoforms in complex samples.”
Quote in the paperSubstantial claim - Premisereasoning§ Proteoforms as the next proteomics currency
Digesting proteins into peptides is crucial for the success and robustness of bottom-up proteomics, since peptides separate and ionize better in liquid chromatography-mass spectrometry than intact proteins.
“The step of digestion into peptides is essential to the success and robustness of the bottom-up strategy, as well-behaved peptides are more amenable to liquid chromatographic separation and MS analysis than are intact proteins.”
Quote in the paperSubstantial claim - Premisecitation§ Proteoforms as the next proteomics currency
Biological systems appear to express far fewer proteoform types and variants than combinatorial calculations would allow.
“However, the number and variety of proteoforms expressed in biological systems appear to be far below the calculated combinatorial possibilities (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Aebersold R Nat. Chem. Biol 14 206 2018 29443976 PMC5837046 source
Not checked in the free run.
- Classified as probably not a substantial claim. 3
- May combine two claims. 4
Classified as probably not a substantial claim. May combine two claims.
Interpretationreasoning§ Proteoforms as the next proteomics currencyThis discrepancy may mean that many or most proteoforms are undetectable with current technology and that only the most abundant are seen.
“This difference may simply indicate that many or most proteoforms are not detectable with current technology, and that we are only able to see at present the few of those that are most abundant.”
Quote in the paperSubstantial claim- Rests on an assumption: Existing mass spectrometers can detect proteoforms only at concentrations above their instrumental detection limits.
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
Interpretationreasoning§ Proteoforms as the next proteomics currencyAlternatively, nature may produce and use only a small subset of the proteoforms that are theoretically possible.
“Alternatively, nature may only make and use a small subset of the proteoforms that are theoretically possible, as deduced from the combinatorial possibilities offered by considering all of the various possible PTM combinations.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Proteoforms as the next proteomics currencyThe 74 identified histone H4 proteoforms contrast with the approximately 3 million possibilities theoretically generated by combinatorial explosion of known site-specific modifications.
“This stands in striking contrast to the ~3 million possibilities that are theoretically possible from the combinatorial explosion of known site-specific modifications (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Phanstiel D Proc. Natl. Acad. Sci. U.S.A 105 4093 2008 18326628 PMC2393763 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Proteoforms as the next proteomics currencyThese pairwise relationships-experimental versus theoretical and experimental versus experimental-were assembled into families of related proteoforms.
“These pairwise relations (experimental:theoretical and experimental:experimental) were assembled into “families” of related proteoforms (see the figure, top center).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Shortreed MR J. Proteome Res 15 1213 2016 26941048 PMC4917391 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Proteoforms as the next proteomics currencyRNA sequencing can build sample-specific proteoform databases that capture genetic variation and splicing patterns, allowing the strategy to be extended to mammalian genomes.
“To extend the strategy to mammalian genomes, RNA sequencing can be used to construct sample-specific proteoform databases that capture the genetic variation and extent of splicing patterns in the sample (10, 11).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Proteoforms as the next proteomics currencyTop-down proteomics has made recent progress on high-mass proteins and complex samples, but limitations remain in sequence coverage and in analyzing low-abundance species.
“Although great strides have recently been made in the topdown analysis of high-mass proteins (7) and complex proteomic samples (8), limitations remain to be addressed in the degree of sequence coverage and the ability to analyze low-abundance species.”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
Protein function can be strongly modulated by posttranslational modifications such as phosphorylation, acetylation, and methylation.
“The function of proteins can be strongly modulated by posttranslational modifications (PTMs) such as phosphorylation (consider kinase cascades), acetylation, methylation (consider histones), and many more of the >400 known PTMs in biology.”
The paper relies on this without support.
In bottom-up proteomics, each identified peptide serves as a surrogate for the presence of the protein molecule from which it was derived.
“Each identified peptide acts as a surrogate for the presence of the protein molecule from which it is derived.”
The paper relies on this without support.
Errors in transcription and translation can produce numerous low-abundance proteoforms, possibly as few as one molecule per cell or one molecule in a large population of cells.
“This question may prove impossible to answer fully, as errors in transcription and translation can produce numerous low-abundance proteoforms, perhaps as few as only a single molecule per cell, or even a single molecule in a large population of cells.”
The paper relies on this without support.
Existing mass spectrometers can detect proteoforms only at concentrations above their instrumental detection limits.
“We currently can only detect proteoforms present at concentrations above the instrumental detection limits of existing mass spectrometers, although the advent of single-molecule nanopore or other strategies for proteoform identification may change that landscape in the future.”
The paper relies on this without support.
Proteoforms are closely connected to how cells and tissues function in complex phenotypes.
“As proteoforms are tightly linked to the functioning of cells and tissues that underlie complex phenotypes, their identification and quantification will provide critical insights into the fundamental workings of biological systems (see the figure, top right).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Protein species outnumber coding genes in eukaryotes, in part, because one gene can encode multiple transcripts through alternative splicing.
“Protein species outnumber coding genes in eukaryotes, in part, because one gene can encode multiple transcripts through alternative splicing (AS) (Aebersold et al., 2018; Smith and Kelleher, 2018).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Smith and Kelleher, 2018
Top-down proteomics avoids inferring proteins from shotgun peptide data and provides cell- and proteoform-specific information.
“In this study, we used top-down proteomics (TDP) (16), which avoids the problem of inferring proteins using peptide data from shotgun proteomics analysis (17), to obtain cell- and proteoform-specific information (18) from the major cell types present in the blood and bone marrow.”
From The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells (2022) · cites this paper as [18]
Mutations, alternative splicing, and PTMs generate many proteoforms from a single gene, greatly diversifying the proteome.
“Mutations, alternative splicing events, and post-translational modifications (PTMs) result in a host of proteoforms (a term referring to all the protein products that arise from a single gene) that greatly diversify the proteome [1–4].”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [1]
Top-down proteomics allows direct analysis of intact proteins without digestion, providing a bird's-eye view of existing proteoforms.
“top-down proteomics allows for direct analysis of intact proteins without digestion, thus providing a “bird’s-eye” view of existing proteoforms (9, 12, 21, 23, 28, 29).”
From Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics (2020) · cites this paper as [12]
Antibody-based approaches heavily rely on prior knowledge of protein targets, and shotgun bottom-up proteomics has intrinsic limitations due to the peptide-to-protein inference problem and is unable to provide proteoform-specific information.
“However, antibody-based approaches heavily rely on prior knowledge of protein targets. While MS-based techniques provide information without a priori knowledge, shotgun bottom-up proteomics has intrinsic limitations due to the “peptide-to-protein” inference problem and is, therefore, unable to provide proteoform-specific information (12, 27).”
From Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics (2020) · cites this paper as [12]
The proteoform hypothesis holds that direct analysis of actual proteins in a living system has a tighter mechanistic connection to biological processes than analysis of proteolytic peptides.
“the so-called “proteoform hypothesis” posits that the direct analysis of the actual proteins present in a living system holds a much tighter mechanistic connection with biological processes than the analysis of their surrogates (i.e., proteolytic peptides).7,8”
From Proton Transfer Charge Reduction Enables High-Throughput Top-Down Analysis of Large Proteoforms (2019) · cites this paper as [8]
Top-down mass spectrometry (MS)-based proteomics provides a comprehensive analysis of proteoforms to achieve a proteome-wide understanding of protein functions.
“Top-down mass spectrometry (MS)-based proteomics provides a comprehensive analysis of proteoforms to achieve a proteome-wide understanding of protein functions.”
From Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum (2020) · cites this paper as [3]
On average, there may be as many as 100 proteoforms per protein, based on possible coding-sequence variations and post-translational modifications.
“it is estimated that there may be up to 100 proteoforms per protein on average.(4,5)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [5]
Top-down proteomics analyzes the entire intact proteoform and is the most powerful proteoform-level analysis technology in existence, providing knowledge regarding RNA isoform translation and combinatorial posttranslational modifications, but is limited in depth and throughput.
“Top-down proteomics, in contrast, analyzes the entire intact proteoform and is the most powerful proteoform-level analysis technology in existence, providing knowledge regarding RNA isoform translation and combinatorial PTMs, but is limited in depth and throughput ( 4 , 6 ).”
From The Human Proteoform Project: Defining the human proteome (2021) · cites this paper as [6]
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- Authors
- Smith, L. M., & Kelleher, N. L.
- Affiliations
- University of Wisconsin–Madison (US)
- Northwestern University (US)
- Venue
- Science
- Published
- 2018-03-09
- Volume
- 359
- Issue
- 6380
- Pages
- 1106-1107
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5944612
- OpenAlex
- W2790214985
- Cited by
- 322
- References
- 14
- Citations by year
- 2026: 36 · 2025: 42 · 2024: 46 · 2023: 46 · 2022: 43 · 2021: 46 · 2020: 31 · 2019: 23 · 2018: 7 · 2012: 1
- FWCI
- 11.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM114292, P41GM108569)
- 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 › Protein Structure and Dynamics
- Keywords
- proteoforms, protein isoforms, protein modification, proteomics, protein function
- MeSH terms
- Animals, Humans, Peptides, Protein Processing, Post-Translational, Genetic Variation, Protein Isoforms, Proteomics
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