The pivotal role of MBD4-ATP7B in the human Cu(i) excretion path as revealed by EPR experiments and all-atom simulations

Zena Qasem; Matic Pavlin; Ida Ritacco; Lada Gevorkyan-Airapetov; Alessandra Magistrato; Sharon Ruthstein

doi:10.1039/c9mt00067d

The pivotal role of MBD4-ATP7B in the human Cu(i) excretion path as revealed by EPR experiments and all-atom simulations

Zena Qasem, Matic Pavlin, Ida Ritacco, Lada Gevorkyan-Airapetov, Alessandra Magistrato, Sharon Ruthstein

National Research Council of Italy

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12 Scopus citations

Abstract

Copper's essentiality and toxicity require a meticulous mechanism for its acquisition, cellular distribution and excretion, which remains hitherto elusive. Herein, we jointly employed electron paramagnetic resonance spectroscopy and all-atom simulations to resolve the copper trafficking mechanism in humans considering the route travelled by Cu(i) from the metallochaperone Atox1 to the metal binding domains 3 and 4 of ATP7B. Our study shows that Cu(i) in the final part of its extraction pathway is most likely mediated by binding of Atox1 monomer to MBD4 of ATP7B. This interaction takes place through weak metal-stabilized protein-protein interactions.

Original language	English
Pages (from-to)	1288-1297
Number of pages	10
Journal	Metallomics
Volume	11
Issue number	7
DOIs	https://doi.org/10.1039/c9mt00067d
State	Published - 17 Jul 2019

Bibliographical note

Publisher Copyright:
© 2019 The Royal Society of Chemistry.

Funding

This work was supported by the Israel and Italian Ministry of Science grant financed to SR and AM and by the ERC-STG grant no. 754365 given to SR. AM thanks the Italian Association for Cancer Research (MFAG grant no. 17134). MP thanks CINECA for computational resources (ISCRA no. HP10BXE6H9). IR thanks AIRC for financial support through a ‘Gianni Bonadonna’ fellowship. AM thanks S. Fabris, S. Piccinin and A. Vanossi for useful discussions.

Funders	Funder number
ERC-STG
Israel and Italian Ministry of Science
Horizon 2020 Framework Programme	754365
Associazione Italiana per la Ricerca sul Cancro	17134

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The pivotal role of MBD4-ATP7B in the human Cu(i) excretion path as revealed by EPR experiments and all-atom simulations

Abstract

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