Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE
Open accessPublished version of a preprint
Abstract
Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.
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References 113 · Cited by 52
- Authors
- Chongsaritsinsuk, J., Steigmeyer, A. D., Mahoney, K. E., Rosenfeld, M. A., Lucas, T. M., Smith, C. M., Li, A., Ince, D., Kearns, F. L., Battison, A. S., Hollenhorst, M. A., Judy Shon, D., Tiemeyer, K. H., Attah, V., Kwon, C., Bertozzi, C. R., Ferracane, M. J., Lemmon, M. A., Amaro, R. E., & Malaker, S. A.
- Affiliations
- Yale University (US)
- University of California San Diego (US)
- Stanford Medicine (US)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- University of Redlands (US)
- Corresponding author
- Malaker, Stacy A.
- ORCID
- Chongsaritsinsuk, Joann
- Steigmeyer, Alexandra D.
- Mahoney, Keira E.
- Rosenfeld, Mia A.
- Lucas, Taryn M.
- Smith, Courtney M.
- Li, Alice
- Ince, Deniz
- Kearns, Fiona L.
- Battison, Alexandria S.
- Hollenhorst, Marie A.
- Judy Shon, D.
- Tiemeyer, Katherine H.
- Bertozzi, Carolyn R.
- Ferracane, Michael J.
- Lemmon, Mark A.
- Amaro, Rommie E.
- Malaker, Stacy A.
- Venue
- Nature Communications
- Published
- 2023-10-04
- Volume
- 14
- Issue
- 1
- Pages
- 6169-6169
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10550946
- OpenAlex
- W4387335304
- Cited by
- 52
- References
- 113
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 14 · 2023: 4
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35-GM147039)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- TIM-3, TIM-4, TIM-1, O-glycosylation, glycoproteomics, protein structural dynamics, ligand binding, immune checkpoint, T cell immunity
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