A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters

Abstract In humans, the H+-coupled Fe2+ transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H+-cotransport has remained elu...

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Autores principales:	Jonai Pujol-Giménez, Matthias A. Hediger, Gergely Gyimesi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf2c702817c54f5998ccf3e24443a3dd
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spelling	oai:doaj.org-article:cf2c702817c54f5998ccf3e24443a3dd2021-12-02T11:52:25ZA novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters10.1038/s41598-017-06446-y2045-2322https://doaj.org/article/cf2c702817c54f5998ccf3e24443a3dd2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06446-yhttps://doaj.org/toc/2045-2322Abstract In humans, the H+-coupled Fe2+ transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H+-cotransport has remained elusive. Here, we used a combination of molecular dynamics simulations, in silico pK a calculations and site-directed mutagenesis, followed by rigorous functional analysis, to discover two previously uncharacterized functionally relevant residues in hDMT1 that contribute to H+-coupling. E193 plays a central role in proton binding, thereby affecting transport properties and electrogenicity, while N472 likely coordinates the metal ion, securing an optimally “closed” state of the protein. Our molecular dynamics simulations provide insight into how H+-translocation through E193 is allosterically linked to intracellular gating, establishing a novel transport mechanism distinct from that of other H+-coupled transporters.Jonai Pujol-GiménezMatthias A. HedigerGergely GyimesiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jonai Pujol-Giménez Matthias A. Hediger Gergely Gyimesi A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
description	Abstract In humans, the H+-coupled Fe2+ transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H+-cotransport has remained elusive. Here, we used a combination of molecular dynamics simulations, in silico pK a calculations and site-directed mutagenesis, followed by rigorous functional analysis, to discover two previously uncharacterized functionally relevant residues in hDMT1 that contribute to H+-coupling. E193 plays a central role in proton binding, thereby affecting transport properties and electrogenicity, while N472 likely coordinates the metal ion, securing an optimally “closed” state of the protein. Our molecular dynamics simulations provide insight into how H+-translocation through E193 is allosterically linked to intracellular gating, establishing a novel transport mechanism distinct from that of other H+-coupled transporters.
format	article
author	Jonai Pujol-Giménez Matthias A. Hediger Gergely Gyimesi
author_facet	Jonai Pujol-Giménez Matthias A. Hediger Gergely Gyimesi
author_sort	Jonai Pujol-Giménez
title	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
title_short	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
title_full	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
title_fullStr	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
title_full_unstemmed	A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters
title_sort	novel proton transfer mechanism in the slc11 family of divalent metal ion transporters
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/cf2c702817c54f5998ccf3e24443a3dd
work_keys_str_mv	AT jonaipujolgimenez anovelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters AT matthiasahediger anovelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters AT gergelygyimesi anovelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters AT jonaipujolgimenez novelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters AT matthiasahediger novelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters AT gergelygyimesi novelprotontransfermechanismintheslc11familyofdivalentmetaliontransporters
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A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters

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