{"doi":"10.7554/elife.86129","title":"Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15","abstract":"Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg 2+ ions on their own and influx of divalent cations when expressed with the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM-binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP and CNNM-binding protein and demonstrate that ARL15 also inhibits CNNM2 Mg 2+ efflux. The crystal structure of a complex between ARL15 and CNNM2 CBS-pair domain reveals the molecular basis for binding and allowed the identification of mutations that specifically block binding. A binding deficient ARL15 mutant, R95A, failed to inhibit CNNM and TRPM7 transport of Mg 2+ and Zn 2+ ions. Structural analysis and binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) showed that ARL15 and PRLs compete for binding CNNM to coordinate regulation of ion transport by CNNM and TRPM7.","journal":"eLife","year":2023,"id":344680,"datarank":0.4448604001420908,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.04900180069980189,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.04900180069980189,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":9,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":true,"deposit_databanks":{"PDB":["8F6D"]},"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":473781,"name":"Guennadi Kozlov","orcid":"0000-0002-7742-6558","position":1,"is_corresponding":false},{"id":706176,"name":"Pengyu Zong","orcid":"0000-0001-7952-113X","position":2,"is_corresponding":false},{"id":1084107,"name":"Emma L Lee","orcid":null,"position":3,"is_corresponding":false},{"id":1083516,"name":"Sandra Tetteh","orcid":"0000-0002-4894-1518","position":4,"is_corresponding":false},{"id":1084108,"name":"Thushara Nethramangalath","orcid":null,"position":5,"is_corresponding":false},{"id":1083517,"name":"Caroline Knorn","orcid":"0000-0001-8275-839X","position":6,"is_corresponding":false},{"id":876716,"name":"Jianning Jiang","orcid":null,"position":7,"is_corresponding":false},{"id":1083518,"name":"Ashkan Shahsavan","orcid":"0009-0002-6465-9560","position":8,"is_corresponding":false},{"id":669398,"name":"Lixia Yue","orcid":"0000-0002-3558-091X","position":9,"is_corresponding":false},{"id":669399,"name":"Loren W. Runnels","orcid":"0000-0002-2537-7360","position":10,"is_corresponding":false},{"id":473784,"name":"Kalle Gehring","orcid":"0000-0001-6500-1184","position":11,"is_corresponding":false},{"id":1083515,"name":"Luba Mahbub","orcid":"0000-0001-7604-6134","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:11:35.133818Z","pmid":"37449820","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":[]}