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CRISPR Reveals the Sugary Secrets of the Cancer Related Notch Protein

저자:   업로드:2017-09-20  조회수:

    The proteins in human cells are extensively decorated with different types of sugars, a phenomenon called glycosylation. These modifications greatly increase the diversity of protein structure and function, affecting how proteins fold, how they behave, and where they go in cells.


    Scientists at the University of Georgia say they have shown that a rare type of glycosylation greatly affects the function of a protein important for human development and cancer progression.




    Protein glycosylation, N-linked or O-linked, depends on whether a sugar is attached to nitrogen- or oxygen-containing sites, respectively. The research team of Robert Haltiwanger, Ph.D., has studied specific O-linked modifications, i.e., the attachment of glucose or fucose to serine or threonine, a modification that affects only a few hundred different types of proteins, including one called Notch. It's a signaling receptor critical for cell development and differentiation and is dysregulated in cancers such as leukemia, breast cancer, and prostate cancer.


    "The fact that we found these sugars on Notch was intriguing because Notch is a very important molecule," Dr. Haltiwanger said. "So, we've been curious about how these sugars affect [Notch's] stability and activity."


    The enzymes responsible for modifying Notch with glucose and fucose are called POFUT1 and POGLUT1. Dr. Haltiwanger's team, led by Hideyuki Takeuchi, Ph.D., wanted to know exactly why POFUT1 and POGLUT1 were attaching glucose and fucose to Notch in cells. They carried out a study ("O-Glycosylation Modulates the Stability of Epidermal Growth Factor-Like Repeats and Thereby Regulates Notch Trafficking"), which is published in the Journal of Biological Chemistry.


    “Here we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat, and that addition of both O-glucose and O-fucose enhances stability in an additive manner,” write the investigators. “Finally, we solved the crystal structure of a single EGF [epidermal growth factor] repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interac

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