{"doi":"10.3390/biom12121816","title":"The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking","abstract":"Alpha-synuclein is a presynaptic protein linked to Parkinson's disease with a poorly characterized physiological role in regulating the synaptic vesicle cycle. Using RBL-2H3 cells as a model system, we earlier reported that wild-type alpha-synuclein can act as both an inhibitor and a potentiator of stimulated exocytosis in a concentration-dependent manner. The inhibitory function is constitutive and depends on membrane binding by the helix-2 region of the lipid-binding domain, while potentiation becomes apparent only at high concentrations. Using structural and functional characterization of conformationally selective mutants via a combination of spectroscopic and cellular assays, we show here that binding affinity for isolated vesicles similar in size to synaptic vesicles is a primary determinant of alpha-synuclein-mediated potentiation of vesicle release. Inhibition of release is sensitive to changes in the region linking the helix-1 and helix-2 regions of the N-terminal lipid-binding domain and may require some degree of coupling between these regions. Potentiation of release likely occurs as a result of alpha-synuclein interactions with undocked vesicles isolated away from the active zone in internal pools. Consistent with this, we observe that alpha-synuclein can disperse vesicles from in vitro clusters organized by condensates of the presynaptic protein synapsin-1.","journal":"Biomolecules","year":2022,"id":270487,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":934737,"name":"Meraj Ramezani","orcid":"0000-0002-2906-4986","position":1,"is_corresponding":false},{"id":239981,"name":"David Snead","orcid":"0000-0001-7839-452X","position":2,"is_corresponding":false},{"id":934738,"name":"Cristian Follmer","orcid":"0000-0001-6178-0432","position":3,"is_corresponding":false},{"id":934739,"name":"Peter J. Chung","orcid":"0000-0002-5187-8281","position":4,"is_corresponding":false},{"id":935260,"name":"Ka Yee Lee","orcid":null,"position":5,"is_corresponding":false},{"id":586330,"name":"David A. Holowka","orcid":null,"position":6,"is_corresponding":false},{"id":585620,"name":"Barbara Baird","orcid":"0000-0003-0151-7899","position":7,"is_corresponding":false},{"id":317552,"name":"David Eliezer","orcid":"0000-0002-1311-7537","position":8,"is_corresponding":false},{"id":934736,"name":"Tapojyoti Das","orcid":"0000-0002-4644-1499","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T00:27:31.019242Z","pmid":"36551244","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":[]}