title: O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding.
abstract: The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation. However, the effects of the other eight O-GlcNAcylation sites that have been identified were unknown. Here, we use a similar synthetic strategy to investigate the consequences of this modification at one of these sites, serine 87. We show that O-GlcNAcylation at this site also inhibits α-synuclein aggregation but to a lesser extent than that for the same modification at threonine 72. However, we also find that this modification does not affect the membrane-binding properties of α-synuclein, which differentiates it from phosphorylation at the same site. These results further support the development of therapies that can elevate O-GlcNAcylation of α-synuclein to slow the progression of Parkinson's disease.
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Yuka E
authors.initials: YE
authors.lastname: Lewis
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Galesic
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Levine
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: De Leon
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Natalie
authors.initials: N
authors.lastname: Lamiri
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Caroline K
authors.initials: CK
authors.lastname: Brennan
authors.affiliation: Department of Chemistry and §Department of Molecular and Computational Biology, University of Southern California , Los Angeles, California 90089-0744, United States.
authors.forename: Matthew R
authors.identifier: 0000-0003-3205-5615
authors.initials: MR
authors.lastname: Pratt
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D002462:Cell Membrane / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D011485:Protein Binding; D012694:Serine / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D012694:Serine; D000117:Acetylglucosamine