| Title: | The conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter |
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| Authors: | ID Janoš, Pavel, Consiglio Nazionale delle ricerche/National Research Council (CNR) -IOM c/o International School for Advanced Studies (SISSA/ISAS), via Bonomea 265, 34136Trieste, Italy (Author)
ID Aupič, Jana, Consiglio Nazionale delle ricerche/National Research Council (CNR) -IOM c/o International School for Advanced Studies (SISSA/ISAS), via Bonomea 265, 34136Trieste, Italy (Author)
ID Ruthstein , Sharon, Department of Chemistry, Faculty of Exact Sciences and the Institute for Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, 5290002, Ramat-Gan, Israel (Author)
ID Magistrato, Alessandra, Consiglio Nazionale delle ricerche/National Research Council (CNR) -IOM c/o International School for Advanced Studies (SISSA/ISAS), via Bonomea 265, 34136Trieste, Italy (Author) |
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| Files: |
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| Language: | English |
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| Work type: | Not categorized |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | UNG - University of Nova Gorica
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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 (Met) 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, our 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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| Keywords: | copper, membrane transporter, molecular dynamics, QM/MM, free energy |
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| Publication version: | Version of Record |
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| Year of publishing: | 2022 |
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| Number of pages: | 8 |
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| Numbering: | 3 |
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| PID: | 20.500.12556/RUNG-7602 |
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| COBISS.SI-ID: | 121416195 |
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| DOI: | DOI: https://doi.org/10.1017/qrd.2022.2 |
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| NUK URN: | URN:SI:UNG:REP:ZPIXYHWJ |
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| Publication date in RUNG: | 15.09.2022 |
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| Views: | 2375 |
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| Downloads: | 0 |
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