title: Effects of desialylation on human α1-acid glycoprotein-ligand interactions.
abstract: Human α1-acid glycoprotein (AGP), an acute-phase glycoprotein, exists predominantly in blood. With its ability to bind basic, lipophilic, and acidic drugs, AGP has served as a drug carrier. It has been shown that the carbohydrate composition of AGP changes in response to tissue injury, inflammation, or infection and can have a great impact on AGP's drug binding activities. The molecular-level details of the effects of desialylation on the AGP conformation and AGP-ligand interactions, however, are unknown. Here we report the use of hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) to reveal the changes in AGP conformational dynamics induced by the removal of terminal sialic acid. HDX-MS also reveals the changes in the conformational dynamics of sialylated and unsialylated AGP upon formation of complexes of holo-AGP with progesterone or propranolol. Our HDX-MS results demonstrate that desialylation stabilizes two loop regions that are exterior to the β-sheet barrel in AGP, and this stabilization minimizes the conformational changes of AGP upon binding with progesterone or propranolol.
authors.affiliation: Bioprocess Measurements Group, Biomolecular Measurement Division, National Institute of Standards and Technology , Gaithersburg, Maryland 20899, United States.
authors.forename: Richard Y-C
authors.initials: RY
authors.lastname: Huang
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Hudgens
mesh_terms: D041961:Deuterium Exchange Measurement; D006031:Glycosylation; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D009961:Orosomucoid / Q000737:chemistry* / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D008024:Ligands; D009961:Orosomucoid; D011374:Progesterone; D011433:Propranolol; D019158:N-Acetylneuraminic Acid