{"doi":"10.1101/2021.06.18.449046","title":"The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation","abstract":"Abstract Yeast Cadmium Factor-1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4Å and 4.0Å in distinct inward-facing open conformations capturing a previously unobserved ordered state of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the lasso domain. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide long-sought after insights into how R-domains control ABCC transporter activity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225540,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9415,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":775398,"name":"Cinthia Millán","orcid":null,"position":1,"is_corresponding":false},{"id":828314,"name":"Samantha I. Zangari","orcid":null,"position":2,"is_corresponding":false},{"id":827961,"name":"Samantha Avila","orcid":"0000-0003-1769-9391","position":3,"is_corresponding":false},{"id":228614,"name":"Dewight Williams","orcid":"0000-0001-8942-8131","position":4,"is_corresponding":false},{"id":699147,"name":"Tarjani Thaker","orcid":"0000-0002-0947-6094","position":5,"is_corresponding":false},{"id":699149,"name":"Thomas Tomasiak","orcid":"0000-0002-5884-5968","position":6,"is_corresponding":false},{"id":774662,"name":"Nitesh Khandelwal","orcid":"0000-0002-6319-8048","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:26.581453Z","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":[]}