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Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations

[Image: see text] ZnT8 is a human zinc(II) transporter expressed at the membrane of secretory granules where it contributes to insulin storage importing zinc ions from the cytosol. In the human population, the two most common ZnT8 variants carry an arginine (R325) or a tryptophan (W325) in position...

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Autores principales: Sala, Davide, Giachetti, Andrea, Rosato, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023586/
https://www.ncbi.nlm.nih.gov/pubmed/33508935
http://dx.doi.org/10.1021/acs.jcim.0c01139
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author Sala, Davide
Giachetti, Andrea
Rosato, Antonio
author_facet Sala, Davide
Giachetti, Andrea
Rosato, Antonio
author_sort Sala, Davide
collection PubMed
description [Image: see text] ZnT8 is a human zinc(II) transporter expressed at the membrane of secretory granules where it contributes to insulin storage importing zinc ions from the cytosol. In the human population, the two most common ZnT8 variants carry an arginine (R325) or a tryptophan (W325) in position 325. The former variant has the most efficient kinetics in zinc transport and has been correlated to a higher risk of developing insulin resistance. On the contrary, the W325 variant is less active and protects against type-2-diabetes. Here, we used molecular dynamics (MD) simulations to investigate the main differences between the R325 and W325 variants in the interaction with zinc(II) ions. Our simulations suggested that the position of the metal ion within the transport site was not the same for the two variants, underlying a different rearrangement of the transmembrane (TM) helices in the channel. The W325 variant featured a peculiar zinc environment not detected in the experimental structures. With respect to conformational dynamics, we observed that the R325 variant was significantly more flexible than W325, with the main role played by the transmembrane domain (TMD) and the C-terminal domain (CTD). This dynamics affected the packing of the TM helices and thus the channel accessibility from the cytosol. The dimer interface that keeps the two TM channels in contact became looser in both variants upon zinc binding to the transport site, suggesting that this may be an important step toward the switch from the inward- to the outward-facing state of the protein.
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spelling pubmed-80235862021-04-07 Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations Sala, Davide Giachetti, Andrea Rosato, Antonio J Chem Inf Model [Image: see text] ZnT8 is a human zinc(II) transporter expressed at the membrane of secretory granules where it contributes to insulin storage importing zinc ions from the cytosol. In the human population, the two most common ZnT8 variants carry an arginine (R325) or a tryptophan (W325) in position 325. The former variant has the most efficient kinetics in zinc transport and has been correlated to a higher risk of developing insulin resistance. On the contrary, the W325 variant is less active and protects against type-2-diabetes. Here, we used molecular dynamics (MD) simulations to investigate the main differences between the R325 and W325 variants in the interaction with zinc(II) ions. Our simulations suggested that the position of the metal ion within the transport site was not the same for the two variants, underlying a different rearrangement of the transmembrane (TM) helices in the channel. The W325 variant featured a peculiar zinc environment not detected in the experimental structures. With respect to conformational dynamics, we observed that the R325 variant was significantly more flexible than W325, with the main role played by the transmembrane domain (TMD) and the C-terminal domain (CTD). This dynamics affected the packing of the TM helices and thus the channel accessibility from the cytosol. The dimer interface that keeps the two TM channels in contact became looser in both variants upon zinc binding to the transport site, suggesting that this may be an important step toward the switch from the inward- to the outward-facing state of the protein. American Chemical Society 2021-01-29 2021-02-22 /pmc/articles/PMC8023586/ /pubmed/33508935 http://dx.doi.org/10.1021/acs.jcim.0c01139 Text en © 2021 American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Sala, Davide
Giachetti, Andrea
Rosato, Antonio
Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title_full Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title_fullStr Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title_full_unstemmed Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title_short Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations
title_sort insights into the dynamics of the human zinc transporter znt8 by md simulations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023586/
https://www.ncbi.nlm.nih.gov/pubmed/33508935
http://dx.doi.org/10.1021/acs.jcim.0c01139
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