ARL15 is a small GTPase that binds to guanosine triphosphate (GTP) and guanosine diphosphate (GDP), cycling between an active GTP-bound state and an inactive GDP-bound state . This cycling is essential for its function as a molecular switch in various cellular processes. ARL15 has been identified as a binding partner of CNNM (Cyclin M) proteins and an inhibitor of divalent cation influx by TRPM7 (Transient Receptor Potential Melastatin 7) .
ARL15 plays a significant role in regulating ion transport, particularly magnesium (Mg²⁺) and zinc (Zn²⁺) ions. It binds to CNNM proteins and inhibits their Mg²⁺ efflux activity . This regulation is crucial for maintaining cellular ion homeostasis, which is vital for various cellular functions, including energy production and protein synthesis .
Recent structural studies have provided insights into the interaction between ARL15 and CNNM proteins. The crystal structure of the ARL15-CNNM2 complex reveals the molecular basis for their binding and identifies specific mutations that can block this interaction . For example, the R95A mutant of ARL15 fails to inhibit CNNM and TRPM7 transport of Mg²⁺ and Zn²⁺ ions .
The regulation of ion transport by ARL15 is essential for various physiological processes. Disruptions in ARL15 function can lead to imbalances in ion homeostasis, which may contribute to various diseases. For instance, ARL15 has been associated with conditions such as cholestasis and spastic paraplegia .