N-glycosylation as a eukaryotic protective mechanism against protein aggregation

• DOI: 10.1126/sciadv.adk8173
• Publication Date: 2024-01-31T18:58:21Z
• Authors: Ramon Duran-Romaña; Bert Houben; Matthias De Vlees...; Nikolaos Louros; Matthew P. Wilson; Gert Matthijs; Joost Schymkowitz; Frederic Rousseau
• Keywords: 0301 basic medicine; Protein Aggregates; 03 medical and health sciences; Glycosylation; Proteome; Biomedicine and Life Sciences; Peptides; Protein Processing, Post-Translational

The tendency for proteins to form aggregates is an inherent part of every proteome and arises from the self-assembly of short protein segments called aggregation-prone regions (APRs). While posttranslational modifications (PTMs) have been implicated in modulating protein aggregation, their direct role in APRs remains poorly understood. In this study, we used a combination of proteome-wide computational analyses and biophysical techniques to investigate the potential involvement of PTMs in aggregation regulation. Our findings reveal that while most PTM types are disfavored near APRs, N-glycosylation is enriched and evolutionarily selected, especially in proteins prone to misfolding. Experimentally, we show that N-glycosylation inhibits the aggregation of peptides in vitro through steric hindrance. Moreover, mining existing proteomics data, we find that the loss of N-glycans at the flanks of APRs leads to specific protein aggregation in Neuro2a cells. Our findings indicate that, among its many molecular functions, N-glycosylation directly prevents protein aggregation in higher eukaryotes.