Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15

Mahbub, Luba; Kozlov, Guennadi; Zong, Pengyu; Lee, Emma L.; Tetteh, Sandra; Nethramangalath, Thushara; Knorn, Caroline; Jiang, Jianning; Shahsavan, Ashkan; Yue, Lixia; Runnels, Loren; Gehring, Kalle

doi:10.7554/elife.86129

Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15

Journal Article · Fri Jul 14 00:00:00 EDT 2023 · eLife

DOI:https://doi.org/10.7554/elife.86129· OSTI ID:2470059

^[1]; ^[1]; Zong, Pengyu ^[2]; Lee, Emma L. ^[1]; Tetteh, Sandra ^[3]; Nethramangalath, Thushara ^[3]; ^[1]; Jiang, Jianning ^[1]; Shahsavan, Ashkan ^[1]; Yue, Lixia ^[2]; ^[3]; ^[1]

McGill University, Montreal, QC (Canada)
University of Connecticut Health Center, Farmington, CT (United States)
Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ (United States)

Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg²⁺ 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 Mg²⁺ 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 Mg²⁺ and Zn²⁺ 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); Natural Sciences and Engineering Research Council of Canada

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470059

Journal Information:: eLife, Journal Name: eLife Vol. 12; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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