Mapping Proteoforms and Protein Complexes From King Cobra Venom Using Both Denaturing and Native Top-down Proteomics
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Characterizing whole proteins by top-down proteomics avoids a step of inference encountered in the dominant bottom-up methodology when peptides are assembled computationally into proteins for identification. The direct interrogation of whole proteins and protein complexes from the venom of Ophiophagus hannah (king cobra) provides a sharply clarified view of toxin sequence variation, transit peptide cleavage sites and post-translational modifications (PTMs) likely critical for venom lethality. A tube-gel format for electrophoresis (called GELFrEE) and solution isoelectric focusing were used for protein fractionation prior to LC-MS/MS analysis resulting in 131 protein identifications (18 more than bottom-up) and a total of 184 proteoforms characterized from 14 protein toxin families. Operating both GELFrEE and mass spectrometry to preserve non-covalent interactions generated detailed information about two of the largest venom glycoprotein complexes: the homodimeric l-amino acid oxidase (∼130 kDa) and the multichain toxin cobra venom factor (∼147 kDa). The l-amino acid oxidase complex exhibited two clusters of multiproteoform complexes corresponding to the presence of 5 or 6 N-glycans moieties, each consistent with a distribution of N-acetyl hexosamines. Employing top-down proteomics in both native and denaturing modes provides unprecedented characterization of venom proteoforms and their complexes. A precise molecular inventory of venom proteins will propel the study of snake toxin variation and the targeted development of new antivenoms or other biotherapeutics.
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Complex-down analysis enabled the characterisation of protein complexes from cobra venom and in some cases allowed identification of glycosylated and metal-bound proteoforms.
“Complex-down analysis enabled the characterisation of protein complexes, and in some cases allowed identification of glycosylated and metal-bound proteoforms.”
From Higher-order structural characterisation of native proteins and complexes by top-down mass spectrometry (2020) · cites this paper as [113]
Kelleher and co-workers demonstrated the use of native GELFrEE coupled to MS for the characterisation of protein complexes from cobra venom.
“Kelleher and co-workers demonstrated the use of native GELFrEE coupled to MS for the characterisation of protein complexes from cobra venom.113”
From Higher-order structural characterisation of native proteins and complexes by top-down mass spectrometry (2020) · cites this paper as [113]
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- Authors
- Melani, R. D., Skinner, O. S., Fornelli, L., Domont, G. B., Compton, P. D., & Kelleher, N. L.
- Affiliations
- Northwestern University (US)
- Universidade Federal do Rio de Janeiro (BR)
- Corresponding author
- Domont, Gilberto B.
- Kelleher, Neil L.
- ORCID
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 15
- Issue
- 7
- Pages
- 2423-2434
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC4937514
- OpenAlex
- W2378145088
- Cited by
- 85
- References
- 70
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 11 · 2023: 4 · 2022: 14 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 5
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W.M. Keck Foundation
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (100.039/2014)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Early Postdoc Mobility)
- National Science Foundation Graduate Research Fellowship (2014171659)
- Foundation for the National Institutes of Health (GM 067193)
- Office for Research at Northwestern University
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Venomous Animal Envenomation and Studies
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- king cobra venom, Ophiophagus hannah, top-down proteomics, proteoforms, protein complexes, L-amino acid oxidase, cobra venom factor, N-glycosylation, post-translational modification, antivenom development, snake venom toxins
- MeSH terms
- Animals, Chromatography, Liquid, Elapid Venoms, Protein Denaturation, Elapidae, Protein Interaction Mapping, Proteomics, L-Amino Acid Oxidase, Tandem Mass Spectrometry
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