Deconvoluting the Functions of Polypeptide N-α-Acetylgalactosaminyltransferase Family Members by Glycopeptide Substrate Profiling
Open accessAbstract
The polypeptide N-alpha-acetylgalactosaminyltransferases (ppGalNAcTs) play a key role in mucin-type O-linked glycan biosynthesis by installing the initial GalNAc residue on the protein scaffold. The preferred substrates and functions of the >20 isoforms in mammals are not well understood. However, current data suggest that glycosylated mucin domains are created by the successive, often hierarchical, action of several specific ppGalNAcTs. Herein we analyzed the glycopeptide substrate preferences of several ppGalNAcT family members using a library screening approach. A 56-member glycopeptide library designed to reflect a diversity of glycan clustering was assayed for substrate activity with ppGalNAcT isoforms using an azido-ELISA. The data suggest that the ppGalNAcTs can be classified into at least four types, which working together, are able to produce densely glycosylated mucin glycoproteins.
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Glycosylation of the synthetic peptide EA2 derived from Rattus norvegicus submandibular apomucin 10 (MUC10) has been demonstrated in various in vitro assays in the presence of soluble GalNAc-T2.
“As an example, glycosylation of the synthetic peptide EA2 (PTTDSTTPAPTTK)—derived from Rattus norvegicus submandibular apomucin 10 (MUC10)—has been demonstrated in various in vitro assays in the presence of soluble GalNAc-T2 [6, 14, 15].”
From High level in vivo mucin-type glycosylation in Escherichia coli (2018) · cites this paper as [14]
O-glycosylation of eukaryotic target sites using a truncated form of human GalNAc-T2 has been shown without altering the target peptide sequence.
“In contrast, O-glycosylation of eukaryotic target sites using a truncated form of the human glycosyltransferase GalNAc-T2 has been shown without altering the target peptide sequence [6, 9, 14, 15].”
From High level in vivo mucin-type glycosylation in Escherichia coli (2018) · cites this paper as [14]
Previous in vitro studies with GalNAc-T2 have identified Thr7 in the synthetic EA2 peptide sequence as a preferred glycosylation site.
“Previous in vitro studies with GalNAc-T2 have identified Thr7 in the synthetic EA2 peptide sequence [14, 15] and Thr9 in the MUC5AC peptide as preferred glycosylation sites [31].”
From High level in vivo mucin-type glycosylation in Escherichia coli (2018) · cites this paper as [14]
GalNAc-T2 has been classified as an early transferase, preferring mono- or un-glycosylated protein substrates.
“GalNAc-T2 has been classified as an early transferase, preferring mono- or un-glycosylated protein substrates [14].”
From High level in vivo mucin-type glycosylation in Escherichia coli (2018) · cites this paper as [14]
Cites
Hagen, K. G. T., & Tran, D. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201807200 · Cited by 89 · see citing works
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Schjoldager, K. T.-B. G., & Clausen, H. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.09.014 · Cited by 193 · see citing works
Fritz, T. A., Raman, J., & Tabak, L. A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513590200 · Cited by 163 · see citing works
Self-citationHigh level in vivo mucin-type glycosylation in Escherichia coli
Mueller, P., Gauttam, R., Raab, N., Handrick, R., Wahl, C., Leptihn, S., Zorn, M., Kussmaul, M., Scheffold, M., Eikmanns, B., et al. (2018) · Microbial Cell Factories · doi:10.1186/s12934-018-1013-9 · Cited by 22 · see citing works
- Authors
- Pratt, M. R., Hang, H. C., Ten Hagen, K. G., Rarick, J., Gerken, T. A., Tabak, L. A., & Bertozzi, C. R.
- Affiliations
- University of California, Berkeley (US)
- Case Western Reserve University (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bertozzi, Carolyn R
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 11
- Issue
- 7
- Pages
- 1009-1016
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2082715212
- Cited by
- 98
- References
- 1
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA078834, R01CA078834)
- National Institute of General Medical Sciences (GM66047, R01GM066047)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- O-glycosylation, substrate specificity, mucin glycoproteins, enzyme classification
- MeSH terms
- Amino Acid Sequence, Animals, Enzyme-Linked Immunosorbent Assay, Glycopeptides, Molecular Sequence Data, Substrate Specificity, N-Acetylgalactosaminyltransferases, Rats
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