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The Conformational Plasticity of the Selectivity Filter Methionines Controls the In-Cell Cu(I) Uptake through the CTR1 transporter

View ORCID ProfilePavel Janoš, View ORCID ProfileJana Aupič, View ORCID ProfileSharon Ruthstein, View ORCID ProfileAlessandra Magistrato
doi: https://doi.org/10.1101/2021.11.04.467269
Pavel Janoš
aCNR-IOM c/o International School for Advanced studies (SISSA/ISAS), via Bonomea 265, 34136, Trieste, Italy
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Jana Aupič
aCNR-IOM c/o International School for Advanced studies (SISSA/ISAS), via Bonomea 265, 34136, Trieste, Italy
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Sharon Ruthstein
bDepartment of Chemistry, Faculty of Exact Sciences, and the, Institute for Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, 5290002, Ramat-Gan, Israel
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Alessandra Magistrato
aCNR-IOM c/o International School for Advanced studies (SISSA/ISAS), via Bonomea 265, 34136, Trieste, Italy
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  • ORCID record for Alessandra Magistrato
  • For correspondence: alessandra.magistrato@sissa.it
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Abstract

Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity Copper Transporter 1 (CTR1), being the main in-cell copper (Cu(I)) entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two Methionine triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake-rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import-rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, these outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted November 04, 2021.
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The Conformational Plasticity of the Selectivity Filter Methionines Controls the In-Cell Cu(I) Uptake through the CTR1 transporter
Pavel Janoš, Jana Aupič, Sharon Ruthstein, Alessandra Magistrato
bioRxiv 2021.11.04.467269; doi: https://doi.org/10.1101/2021.11.04.467269
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The Conformational Plasticity of the Selectivity Filter Methionines Controls the In-Cell Cu(I) Uptake through the CTR1 transporter
Pavel Janoš, Jana Aupič, Sharon Ruthstein, Alessandra Magistrato
bioRxiv 2021.11.04.467269; doi: https://doi.org/10.1101/2021.11.04.467269

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