Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter

Bozzi, Aaron T.; Zimanyi, Christina M.; Nicoludis, John M.; Lee, Brandon K.; Zhang, Casey H.; Gaudet, Rachelle

doi:10.7554/elife.41124

Title: Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter

Journal Article · 03 February 2019 · eLife

DOI: https://doi.org/10.7554/elife.41124 · OSTI ID:1628897

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^[2]; Lee, Brandon K. ^[2]; Zhang, Casey H. ^[2];

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Harvard Univ., Cambridge, MA (United States); DOE/OSTI
Harvard Univ., Cambridge, MA (United States)

Nramp family transporters—expressed in organisms from bacteria to humans—enable uptake of essential divalent transition metals via an alternating-access mechanism that also involves proton transport. We present high-resolution structures of Deinococcus radiodurans (Dra)Nramp in multiple conformations to provide a thorough description of the Nramp transport cycle by identifying the key intramolecular rearrangements and changes to the metal coordination sphere. Strikingly, while metal transport requires cycling from outward- to inward-open states, efficient proton transport still occurs in outward-locked (but not inward-locked) DraNramp. We propose a model in which metal and proton enter the transporter via the same external pathway to the binding site, but follow separate routes to the cytoplasm, which could facilitate the co-transport of two cationic species. Our results illustrate the flexibility of the LeuT fold to support a broad range of substrate transport and conformational change mechanisms.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Institute of General Medical Sciences; Memorial Fund for Medical Research

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1628897

Journal Information:: eLife, Journal Name: eLife Vol. 8; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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The Rocking Bundle: A Mechanism for Ion-Coupled Solute Flux by Symmetrical Transporters Forrest, Lucy R.; Rudnick, Gary Physiology, Vol. 24, Issue 6 https://doi.org/10.1152/physiol.00030.2009	journal	December 2009
Mechanisms of Glutamate Transport Vandenberg, Robert J.; Ryan, Renae M. Physiological Reviews, Vol. 93, Issue 4 https://doi.org/10.1152/physrev.00007.2013	journal	October 2013
The Amino Acid-Polyamine-Organocation Superfamily Wong, Foon H.; Chen, Jonathan S.; Reddy, Vamsee Journal of Molecular Microbiology and Biotechnology, Vol. 22, Issue 2 https://doi.org/10.1159/000338542	journal	January 2012
A Spontaneous, Recurrent Mutation in Divalent Metal Transporter-1 Exposes a Calcium Entry Pathway Xu, Haoxing; Jin, Jie; DeFelice, Louis J. PLoS Biology, Vol. 2, Issue 3 https://doi.org/10.1371/journal.pbio.0020050	journal	March 2004
The Extended Cleavage Specificity of Human Thrombin Gallwitz, Maike; Enoksson, Mattias; Thorpe, Michael PLoS ONE, Vol. 7, Issue 2 https://doi.org/10.1371/journal.pone.0031756	journal	February 2012
Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters Perez, Camilo; Ziegler, Christine Biological Chemistry, Vol. 394, Issue 5 https://doi.org/10.1515/hsz-2012-0336	journal	May 2013
X-Ray Diffraction data from Deinococcus radiodurans MntH in complex with Fab, source of 5KTE structure Weihofen, Wilhelm SBGrid Data Bank https://doi.org/10.15785/sbgrid/332	dataset	January 2016
X-Ray Diffraction data from Deinococcus radiodurans Nramp/MntH divalent transition metal transporter in the outward-open, mangan, source of 6BU5 structure Bozzi, Aaron T.; Gaudet, Rachelle; Nicoludis, John M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/564	dataset	January 2019
X-Ray Diffraction data from Deinococcus radiodurans Nramp/MntH divalent transition metal transporter mutant G45R, source of 6C3I structure Zimanyi, Christina M. SBGrid Data Bank https://doi.org/10.15785/sbgrid/567	dataset	January 2019
X-Ray Diffraction data from Deinococcus radiodurans Nramp/MntH divalent transition metal transporter mutant G223W, apo, source of 6D91 structure Bozzi, Aaron T. SBGrid Data Bank https://doi.org/10.15785/sbgrid/576	dataset	January 2019
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
How do transporters couple solute movements? Rudnick, Gary Molecular Membrane Biology, Vol. 30, Issue 7 https://doi.org/10.3109/09687688.2013.842658	journal	September 2013
Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M. ETH Zurich https://doi.org/10.3929/ethz-b-000128272	text	January 2017
Evolutionary analysis of Slc11 mechanism of proton-coupled metal-ion transmembrane import F. M. Cellier, Mathieu AIMS Biophysics, Vol. 3, Issue 2 https://doi.org/10.3934/biophy.2016.2.286	journal	January 2016
Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition-metal ion transport Ehrnstorfer, Ines A.; Geertsma, Eric R.; Pardon, Els Nature Publishing Group https://doi.org/10.5167/uzh-102019	text	January 2014
Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M. Nature Publishing Group https://doi.org/10.5167/uzh-136636	text	January 2017
Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters Perez, Camilo; Ziegler, Christine de Gruyter https://doi.org/10.5451/unibas-ep56043	text	January 2013
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013
A general method for determining secondary active transporter substrate stoichiometry Fitzgerald, Gabriel A.; Mulligan, Christopher; Mindell, Joseph A. eLife, Vol. 6 https://doi.org/10.7554/eLife.21016	journal	January 2017
A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters. Pujol Gimenez, Jonai; Hediger, Matthias; Gyimesi, Gergely Nature Publishing Group https://doi.org/10.7892/boris.106119	text	January 2017
Dissecting the proton transport pathway in electrogenic Na + /H + antiporters Uzdavinys, Povilas; Coinçon, Mathieu; Nji, Emmanuel National Academy of Sciences NAS https://doi.org/10.7892/boris.112612	text	January 2017
Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes Mackenzie, Bryan; Ujwal, M. L.; Chang, Min-Hwang Springer-Verlag; http://www.springer.de https://doi.org/10.7892/boris.20376	text	January 2006

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Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds Manatschal, Cristina; Pujol-Giménez, Jonai; Poirier, Marion eLife, Vol. 8 https://doi.org/10.7554/elife.51913	journal	December 2019
Transmembrane helix 6b links proton and metal release pathways and drives conformational change in an Nramp-family transition metal transporter Bozzi, Aaron T.; McCabe, Anne L.; Barnett, Benjamin C. Journal of Biological Chemistry, Vol. 295, Issue 5 https://doi.org/10.1016/s0021-9258(17)49881-4	journal	January 2020
Transmembrane helix 6b links proton and metal release pathways and drives conformational change in an Nramp-family transition metal transporter Bozzi, Aaron T.; McCabe, Anne L.; Barnett, Benjamin C. Journal of Biological Chemistry, Vol. 295, Issue 5 https://doi.org/10.1074/jbc.ra119.011336	journal	December 2019
Unique structural features in an Nramp metal transporter impart substrate-specific proton cotransport and a kinetic bias to favor import Bozzi, Aaron T.; Bane, Lukas B.; Zimanyi, Christina M. Journal of General Physiology, Vol. 151, Issue 12 https://doi.org/10.1085/jgp.201912428	journal	October 2019
Unconventional transport of metal ions and protons by Nramps Rudnick, Gary Journal of General Physiology, Vol. 151, Issue 12 https://doi.org/10.1085/jgp.201912464	journal	November 2019
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds Manatschal, Cristina; Pujol-Giménez, Jonai; Poirier, Marion eLife Sciences Publications Ltd. https://doi.org/10.5167/uzh-181182	text	January 2019
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds Manatschal, Cristina; Pujol-Giménez, Jonai; Poirier, Marion eLife, Vol. 8 https://doi.org/10.7554/elife.51913	journal	December 2019
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds. Manatschal, Cristina; Pujol-Giménez, Jonai; Poirier, Marion eLife Sciences Publications https://doi.org/10.7892/boris.137207	text	January 2019

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