Work

Tyrosine O-GalNAc Alters the Conformation and Proteolytic Susceptibility of APP Model Glycopeptides

Year: 2021

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 O -glycosylation in APP’s proteolytic processing. Therefore, we synthesized native and Swedish-double-mutated APP (glyco)peptides with Tyr 681 - O -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 O -glycosylation induced conformational changes. The Swedish mutation and Tyr 681 - O -GalNAc were the key factors driving conformational changes. Furthermore, the level of α- and β-secretase activity was increased by the presence of mutation and this effect was more pronounced for its glycosylated analogues. Our results suggest that O -glycosylation of Tyr 681 can induce a conformational change in APP and affect its proteolytic processing fate toward the amyloidogenic pathway.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.1c00387

Authors: YashoNandini Singh, David Ormaza, Alessandra Massetti, Dmitriy Minond, Maré Cudic

Institutions: Florida Atlantic University, Nova Southeastern University

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,000