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Exploring the Gating Mechanism of the Human Copper Transporter, hCtr1, Using EPR Spectroscopy
Shahaf Peleg1, Shelly Meron1, Yulia Shenberger1
1Department of Chemistry and Institute of Nanotechnology and Advanced Materials, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Biomolecules
|January 25, 2025
Summary
Human copper transporter 1 (hCtr1) undergoes conformational changes to facilitate copper uptake. Cu(I) binding causes extracellular domains to move inward, suggesting a gating mechanism regulated by membrane lipid composition.
Area of Science:
- Biochemistry
- Biophysics
- Cell Biology
Background:
- Human copper transporter 1 (hCtr1) is essential for cellular copper uptake.
- Previous studies elucidated the transmembrane domain structure but lacked insight into copper transfer and gating mechanisms.
- The role of extracellular domains and full-length hCtr1 conformation remains poorly understood.
Purpose of the Study:
- To investigate the conformational changes in the extracellular N-terminal domain of full-length hCtr1.
- To understand the role of Cu(I) binding in regulating hCtr1 conformational dynamics.
- To explore the influence of membrane environment on hCtr1 gating.
Main Methods:
- Distance electron paramagnetic resonance (DEER) spectroscopy.
- In vitro studies using reconstituted protein in micelles.
- In cell studies using native cell membranes.
Main Results:
- Cu(I) binding induces inward movement of extracellular chains towards the lumen.
- Intracellular domains penetrate the lumen at specific Cu(I) concentrations, indicating a ball-and-chain gating mechanism.
- Conformational changes and gating were observed in both micelles and native membranes, with slight variations suggesting lipid regulation.
Conclusions:
- Cu(I) binding triggers conformational changes in hCtr1 extracellular domains to facilitate copper transfer.
- A ball-and-chain gating mechanism is proposed for hCtr1.
- Membrane lipid composition plays a regulatory role in the hCtr1 gating mechanism.
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