{"doi":"10.1101/2023.08.22.553867","title":"Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms","abstract":"Abstract Magnesium ions (Mg 2+ ) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg 2+ . MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg 2+ into the mitochondrial matrix and regulates Mg 2+ homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg 2+ into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg 2+ translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we determined the structure of human MRS2 in the presence and absence of Mg 2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identified R332 and M336 as major gating residues, which were then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds was found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg 2+ -binding sites were identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg 2+ translocation and regulatory mechanisms of MRS2.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":410725,"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":0.9539,"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":1047141,"name":"Jayashree Balaraman","orcid":"0009-0004-5329-5663","position":1,"is_corresponding":false},{"id":805427,"name":"Fei Zhou","orcid":"0000-0001-6657-7433","position":2,"is_corresponding":false},{"id":259847,"name":"Doreen Matthies","orcid":"0000-0001-9221-4484","position":3,"is_corresponding":false},{"id":992515,"name":"Louis Tung Faat Lai","orcid":"0000-0003-1413-7035","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T01:21:35.071397Z","pmid":"37662257","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":[]}