{"doi":"10.1021/acs.jpcb.9b11720","title":"Effect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau","abstract":"The microtubule-associated protein Tau (MAPT) is a phosphoprotein in neurons of the brain. Aggregation of Tau is the leading cause of tauopathies such as Alzheimer’s disease. Tau undergoes several post-translational modifications of which phosphorylation and O-GlcNAcylation are key chemical modifications. Tau aggregates into paired helical filaments and neurofibrillary tangles upon hyperphosphorylation, whereas O-GlcNAcylation stabilizes the soluble form of Tau. How specific phosphorylation and/or O-GlcNAcylation events influence Tau conformations remains largely unknown due to the disordered nature of Tau. In this study, we have investigated the phosphorylation- and O-GlcNAcylation-induced conformational effects on a Tau segment (Tau225–246) from the proline-rich domain (P2), by performing metadynamics simulations. We study two different phosphorylation patterns: Tau225–246, phosphorylated at T231 and S235, and Tau225–246, phosphorylated at T231, S235, S237, and S238. We also study O-GlcNAcylation at T231 and S235. We find that phosphorylation leads to the formation of strong salt-bridge contacts with adjacent lysine and arginine residues, which disrupts the native β-sheet structure observed in Tau225–246. We also observe the formation of a transient α-helix (238SAKSRLQ244) when Tau225–246 is phosphorylated at four sites. In contrast, O-GlcNAcylation shows only modest structural effects, and the resultant structure resembles the native form of the peptide. Our studies suggest the opposing structural effects of both protein post-translational modifications (PTMs) and the importance of salt bridges in governing the conformational preferences upon phosphorylation, highlighting the role of proximal arginine and lysine upon hyperphosphorylation.","journal":"The Journal of Physical Chemistry B","year":2020,"id":96969,"datarank":0.5289540786924243,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.0,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231182,"name":"Jeetain Mittal","orcid":"0000-0002-9725-6402","position":1,"is_corresponding":false},{"id":480382,"name":"Sairam S. Mallajosyula","orcid":"0000-0002-6825-0378","position":2,"is_corresponding":false},{"id":480381,"name":"Lata Rani","orcid":"0000-0003-2591-2893","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:35:34.520494Z","pmid":"32065850","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":[]}