Intrinsically disordered ectodomain modulates ion permeation through a metal transporter

Area of Science:

• Biochemistry
• Biophysics
• Structural Biology

Background:

• Intrinsically disordered regions (IDRs) enhance the function of channels and transporters through conformational flexibility.
• Copper transporter 1 (Ctr1) is crucial for cellular copper(I) ion uptake in eukaryotes.
• Ctr1 possesses intrinsically disordered regions at its N-terminal (Nterm) and C-terminal ends, with the Nterm mediating extracellular copper delivery.

Purpose of the Study:

• To elucidate the molecular mechanism by which the Nterm of Ctr1 facilitates copper ion transport.
• To investigate the role of intrinsically disordered regions in the conformational dynamics of Ctr1.
• To understand how copper ions and the lipid environment influence Ctr1 function.

Main Methods:

• Advanced molecular dynamics (MD) simulations.
• Circular dichroism (CD) experiments.
• Integration of computational and experimental approaches.

Main Results:

• Copper(I) ions and a lipidic environment induce the insertion of the Ctr1 Nterm into the selectivity filter.
• This insertion event leads to the opening of the Ctr1 channel.
• A lipid-mediated conformational switch in a transmembrane helix propagates to the cytosolic gate, modulating ion transport.

Conclusions:

• The conformational plasticity of IDRs is essential for modulating ion transport in Ctr1.
• Copper ions and lipid interactions are key drivers of Ctr1 channel gating.
• This study provides a molecular mechanism for copper transport mediated by Ctr1's disordered N-terminal region.