{"doi":"10.1101/2023.02.25.530047","title":"N-Glycosylation is a Potent Regulator of Prion Protein Neurotoxicity","abstract":"Abstract The C-terminal domain of cellular prion protein (PrP C ) contains two N-linked glycosylation sites, the occupancy of which impacts disease pathology. In this study, we demonstrate that glycans at these sites are required to maintain an intramolecular interaction with the N-terminal domain, mediated through a previously identified copper-histidine tether, which suppresses the neurotoxic activity of PrP C . NMR and EPR spectroscopy demonstrate that the glycans refine the structure of the protein’s interdomain interaction. Using whole-cell patch-clamp electrophysiology, we further show that cultured cells expressing PrP molecules with mutated glycosylation sites display large, spontaneous inward currents, a correlate of PrP-induced neurotoxicity. Our findings establish a structural basis for the role of N-linked glycans in maintaining a non-toxic, physiological fold of PrP C .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395901,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1080516,"name":"Pooja Jorwal","orcid":null,"position":1,"is_corresponding":false},{"id":353114,"name":"Natalia C. Ubilla‐Rodriguez","orcid":"0000-0003-0411-8674","position":2,"is_corresponding":false},{"id":793846,"name":"Tufa E. Assafa","orcid":"0000-0003-2352-685X","position":3,"is_corresponding":false},{"id":889718,"name":"Jean R.P. Gatdula","orcid":"0000-0003-4322-3880","position":4,"is_corresponding":false},{"id":353116,"name":"David A. Harris","orcid":"0000-0002-6985-5790","position":5,"is_corresponding":false},{"id":266178,"name":"Glenn L. Millhauser","orcid":"0000-0003-2442-7220","position":6,"is_corresponding":false},{"id":354673,"name":"Kevin M. Schilling","orcid":null,"position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T01:19:27.044553Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}