Dynamical interplay between the human high-affinity copper transporter hCtr1 and its cognate metal ion.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
05 04 2022
05 04 2022
Historique:
received:
31
08
2021
revised:
12
10
2021
accepted:
17
02
2022
pubmed:
25
2
2022
medline:
9
4
2022
entrez:
24
2
2022
Statut:
ppublish
Résumé
Abnormal cellular copper levels have been clearly implicated in genetic diseases, cancer, and neurodegeneration. Ctr1, a high-affinity copper transporter, is a homotrimeric integral membrane protein that provides the main route for cellular copper uptake. Together with a sophisticated copper transport system, Ctr1 regulates Cu(I) metabolism in eukaryotes. Despite its pivotal role in normal cell function, the molecular mechanism of copper uptake and transport via Ctr1 remains elusive. In this study, electron paramagnetic resonance (EPR), UV-visible spectroscopy, and all-atom simulations were employed to explore Cu(I) binding to full-length human Ctr1 (hCtr1), thereby elucidating how metal binding at multiple distinct sites affects the hCtr1 conformational dynamics. We demonstrate that each hCtr1 monomer binds up to five Cu(I) ions and that progressive Cu(I) binding triggers a marked structural rearrangement in the hCtr1 C-terminal region. The observed Cu(I)-induced conformational remodeling suggests that the C-terminal region may play a dual role, serving both as a channel gate and as a shuttle mediating the delivery of copper ions from the extracellular hCtr1 selectivity filter to intracellular metallochaperones. Our findings thus contribute to a more complete understanding of the mechanism of hCtr1-mediated Cu(I) uptake and provide a conceptual basis for developing mechanism-based therapeutics for treating pathological conditions linked to de-regulated copper metabolism.
Identifiants
pubmed: 35202609
pii: S0006-3495(22)00157-6
doi: 10.1016/j.bpj.2022.02.033
pmc: PMC9034245
pii:
doi:
Substances chimiques
Cation Transport Proteins
0
Copper Transport Proteins
0
Copper Transporter 1
0
Ions
0
SLC31A1 protein, human
0
Copper
789U1901C5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1194-1204Informations de copyright
Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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