Intrinsically disordered ectodomain modulates ion permeation through a metal transporter

The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm's disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport.