ArticleGlycobiology2017
Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations.
Article in Glycobiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 45 citations in OpenAlex.
- ER quality control of Crumbs2 and Notch proteins by GXYLT1-dependent xylosyl elongation of O-glucose glycans.The Journal of biological chemistry · 2026Article
- Enzyme Reset: Water-Mediated Tautomerization Restores the Catalytic Asparagine in ProteinJournal of chemical information and modeling · 2026Article
- Exploiting human fucosyltransferase 8 allostery with a covalent inhibitor for core fucosylation suppression.Nature communications · 2026Article
- Structure, function, and implications of fucosyltransferases in health and disease.Nature communications · 2025Review
- DifferentialProceedings of the National Academy of Sciences of the United States of America · 2025Article
- ProteinMolecules (Basel, Switzerland) · 2025Review
- POFUT1 promotes gastric cancer progression through Notch/Wnt dual signaling pathways dependent on the parafibromin-NICD1-β-catenin complex.Journal of the Chinese Medical Association : JCMA · 2023Article
- In silico modelling of the function of disease-related CAZymes.Essays in biochemistry · 2023Article
- L-fucose, a sugary regulator of antitumor immunity and immunotherapies.Molecular carcinogenesis · 2022Review
- Significant Roles of NotchMolecules (Basel, Switzerland) · 2022Review
- Modulation of the NOTCH1 Pathway by LUNATIC FRINGE Is Dominant over That of MANIC or RADICAL FRINGE.Molecules (Basel, Switzerland) · 2021Article
- The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation.Biomolecules · 2021Review
- Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way, but It Is Still a Long Way Down.Molecules (Basel, Switzerland) · 2021Review
- Asparagine Tautomerization in Glycosyltransferase Catalysis. The Molecular Mechanism of ProteinACS catalysis · 2021Article
- ProteinMolecules (Basel, Switzerland) · 2021Article
- Other Types of Glycosylation.Advances in experimental medicine and biology · 2021Article
- Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases.The Journal of biological chemistry · 2020Article
- Differential Labeling of Glycoproteins with Alkynyl Fucose Analogs.International journal of molecular sciences · 2020Article
- Comparative Genomic Analysis of Rapidly Evolving SARS-CoV-2 Reveals Mosaic Pattern of Phylogeographical Distribution.mSystems · 2020Article
- Article
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7 authors at 1 institution in 1 country.
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Abstract
Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function. CRISPR-mediated knockout of POFUT1 in U2OS cells suppresses both normal Notch1 signaling, and the ligand-independent signaling associated with leukemogenic mutations of Notch1. Normal and oncogenic signaling are rescued by wild-type POFUT1 but rescue is impaired by an active-site R240A mutation. The overall structure of the human enzyme closely resembles that of the Caenorhabditis elegans protein, with an overall backbone RMSD of 0.93 Å, despite primary sequence identity of only 39% in the mature protein. GDP-fucose binding to the human enzyme induces limited backbone conformational movement, though the side chains of R43 and D244 reorient to make direct contact with the fucose moiety in the complex. The reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1-/- background. Together, these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition.
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