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Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study

[Image: see text] Atox1 is a human copper metallochaperone that is responsible for transferring copper ions from the main human copper transporter, hCtr1, to ATP7A/B in the Golgi apparatus. Atox1 interacts with the Ctr1 C-terminal domain as a dimer, although it transfers the copper ions to ATP7A/B i...

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Autores principales: Perkal, Ortal, Qasem, Zena, Turgeman, Meital, Schwartz, Renana, Gevorkyan-Airapetov, Lada, Pavlin, Matic, Magistrato, Alessandra, Major, Dan Thomas, Ruthstein, Sharon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294806/
https://www.ncbi.nlm.nih.gov/pubmed/32396355
http://dx.doi.org/10.1021/acs.jpcb.0c01744
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author Perkal, Ortal
Qasem, Zena
Turgeman, Meital
Schwartz, Renana
Gevorkyan-Airapetov, Lada
Pavlin, Matic
Magistrato, Alessandra
Major, Dan Thomas
Ruthstein, Sharon
author_facet Perkal, Ortal
Qasem, Zena
Turgeman, Meital
Schwartz, Renana
Gevorkyan-Airapetov, Lada
Pavlin, Matic
Magistrato, Alessandra
Major, Dan Thomas
Ruthstein, Sharon
author_sort Perkal, Ortal
collection PubMed
description [Image: see text] Atox1 is a human copper metallochaperone that is responsible for transferring copper ions from the main human copper transporter, hCtr1, to ATP7A/B in the Golgi apparatus. Atox1 interacts with the Ctr1 C-terminal domain as a dimer, although it transfers the copper ions to ATP7A/B in a monomeric form. The copper binding site in the Atox1 dimer involves Cys12 and Cys15, while Lys60 was also suggested to play a role in the copper binding. We recently showed that Atox1 can adopt various conformational states, depending on the interacting protein. In the current study, we apply EPR experiments together with hybrid quantum mechanics–molecular mechanics molecular dynamics simulations using a recently developed semiempirical density functional theory approach, to better understand the effect of Atox1’s conformational states on copper coordination. We propose that the flexibility of Atox1 occurs owing to protonation of one or more of the cysteine residues, and that Cys15 is an important residue for Atox1 dimerization, while Cys12 is a critical residue for Cu(I) binding. We also show that Lys60 electrostatically stabilizes the Cu(I)–Atox1 dimer.
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spelling pubmed-72948062020-06-16 Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study Perkal, Ortal Qasem, Zena Turgeman, Meital Schwartz, Renana Gevorkyan-Airapetov, Lada Pavlin, Matic Magistrato, Alessandra Major, Dan Thomas Ruthstein, Sharon J Phys Chem B [Image: see text] Atox1 is a human copper metallochaperone that is responsible for transferring copper ions from the main human copper transporter, hCtr1, to ATP7A/B in the Golgi apparatus. Atox1 interacts with the Ctr1 C-terminal domain as a dimer, although it transfers the copper ions to ATP7A/B in a monomeric form. The copper binding site in the Atox1 dimer involves Cys12 and Cys15, while Lys60 was also suggested to play a role in the copper binding. We recently showed that Atox1 can adopt various conformational states, depending on the interacting protein. In the current study, we apply EPR experiments together with hybrid quantum mechanics–molecular mechanics molecular dynamics simulations using a recently developed semiempirical density functional theory approach, to better understand the effect of Atox1’s conformational states on copper coordination. We propose that the flexibility of Atox1 occurs owing to protonation of one or more of the cysteine residues, and that Cys15 is an important residue for Atox1 dimerization, while Cys12 is a critical residue for Cu(I) binding. We also show that Lys60 electrostatically stabilizes the Cu(I)–Atox1 dimer. American Chemical Society 2020-05-12 2020-06-04 /pmc/articles/PMC7294806/ /pubmed/32396355 http://dx.doi.org/10.1021/acs.jpcb.0c01744 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Perkal, Ortal
Qasem, Zena
Turgeman, Meital
Schwartz, Renana
Gevorkyan-Airapetov, Lada
Pavlin, Matic
Magistrato, Alessandra
Major, Dan Thomas
Ruthstein, Sharon
Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title_full Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title_fullStr Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title_full_unstemmed Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title_short Cu(I) Controls Conformational States in Human Atox1 Metallochaperone: An EPR and Multiscale Simulation Study
title_sort cu(i) controls conformational states in human atox1 metallochaperone: an epr and multiscale simulation study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294806/
https://www.ncbi.nlm.nih.gov/pubmed/32396355
http://dx.doi.org/10.1021/acs.jpcb.0c01744
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