O-glycosylation of Epidermal Growth Factor-like (EGF) repeats plays crucial roles in protein folding, trafficking and function. The Notch extracellular domain has been used as a model to study these mechanisms due to its many O-glycosylated EGF repeats. Three enzymes were previously known to O-glycosylate Notch EGF repeats: Protein O-Glucosyltransferase 1 (POGLUT1), Protein O-Fucosyltransferase 1 (POFUT1), and EGF Domain Specific O-Linked N-Acetylglucosamine Transferase (EOGT). All of these modifications affect Notch activity. Recently, POGLUT2 and POGLUT3 were identified as two novel O-glucosyltransferases that modify a few Notch EGF repeats at sites distinct from those modified by POGLUT1. Comparison of these modification sites revealed a putative consensus sequence which predicted modification of many extracellular matrix proteins including fibrillins (FBNs) and Latent TGFβ-binding proteins (LTBPs). Glycoproteomic analysis revealed that approximately half of the 47 EGF repeats in FBN1 and FBN2, and half of the 18 EGF repeats in LTBP1, are modified by POGLUT2 and/or POGLUT3. Cellular assays showed that loss of modifications by POGLUT2 and/or POGLUT3 significantly reduces FBN1 secretion. There is precedent for EGF modifications to affect protein–protein interactions, as has been demonstrated by research of POGLUT1 and POFUT1 modifications on Notch. Here we discuss the identification and characterization of POGLUT2 and POGLUT3 and the ongoing research that continues to elucidate the biological significance of these novel enzymes.
The flower represents the Drosophila testis niche with the hub cells at the center. Each petal of the flower represents Germline stem cells (GSCs) with a large and a smaller purple circle representing centromere; green rays representing stronger centromeres preferentially attach to the niche. Red and green caterpillars represent sister chromatids in prometaphase with separable old and new H3 in GSCs. Further, large butterflies closer to the flower represent prometaphase GSCs with a red wing vs a green wing representing non-overlapping old and new H3. Small orange butterflies away from the flower represent prophase gonialblast cells with overlapping old and new H3 signals. The background is from coiled sperm from the fly testis. Cover art generated by Professor Tim Phelps.
Identification, function, and biological relevance of POGLUT2 and POGLUT3
Daniel B. Williamson, Robert S. Haltiwanger; Identification, function, and biological relevance of POGLUT2 and POGLUT3. Biochem Soc Trans 29 April 2022; 50 (2): 1003–1012. doi: https://doi.org/10.1042/BST20210850
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