biostudies-literatureSingh YFlorida Atlantic UniversityNational Cancer InstituteNCI NIH HHS2974-2980https://www.ebi.ac.uk/biostudies/studies/S-EPMC8378340biostudies-literatureUnknown12(16)The amyloid-β precursor protein (APP) undergoes proteolytic cleavage by α-, β-, and γ-secretases, to determine its fate in Alzheimer's disease (AD) pathogenesis. Recent findings suggest a possible role of <i>O</i>-glycosylation in APP's proteolytic processing. Therefore, we synthesized native and Swedish-double-mutated APP (glyco)peptides with Tyr⁶⁸¹-<i>O</i>-GalNAc. We studied conformational changes and proteolytic processing using circular dichroism (CD) spectroscopy and enzyme cleavage assay, respectively. CD analysis was carried out in four solvent systems to evaluate peptide environment and <i>O</i>-glycosylation induced conformational changes. The Swedish mutation and Tyr⁶⁸¹-<i>O</i>-GalNAc were the key factors driving conformational changes. Furthermore, the leACS chemical neuroscienceTyrosine <i>O</i>-GalNAc Alters the Conformation and Proteolytic Susceptibility of APP Model Glycopeptides.PMC8378340R15 CA249788R15CA242351R15CA249788R15 CA242351Ormaza DSingh YMassetti ACudic MMinond DfalseTyrosine <i>O</i>-GalNAc Alters the Conformation and Proteolytic Susceptibility of APP Model Glycopeptides.The amyloid-β precursor protein (APP) undergoes proteolytic cleavage by α-, β-, and γ-secretases, to determine its fate in Alzheimer's disease (AD) pathogenesis. Recent findings suggest a possible role of <i>O</i>-glycosylation in APP's proteolytic processing. Therefore, we synthesized native and Swedish-double-mutated APP (glyco)peptides with Tyr⁶⁸¹-<i>O</i>-GalNAc. We studied conformational changes and proteolytic processing using circular dichroism (CD) spectroscopy and enzyme cleavage assay, respectively. CD analysis was carried out in four solvent systems to evaluate peptide environment and <i>O</i>-glycosylation induced conformational changes. The Swedish mutation and Tyr⁶⁸¹-<i>O</i>-GalNAc were the key factors driving conformational changes. Furthermore, the le2021-01-01T00:00:00Z2021 Aug2025-04-18T15:45:04.187Z2024-11-10T07:10:10.878ZS-EPMC83783403432428910.1021/acschemneuro.1c00387