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  • 1.
    Aziz-Qureshi, Abdul
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Meier, Pascal F.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lee, Chiara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The MEMbrane Protein Single ShoT Amplification Recipe: MemStar2017In: A Structure-Function Toolbox for Membrane Transporter and Channels / [ed] Christine Ziegler, San Diego: Elsevier, 2017, Vol. 594, p. 123-138Chapter in book (Refereed)
    Abstract [en]

    Here, we present a simple overexpression condition for high-throughput screening of membrane proteins in Escherichia coli. For the vast majority of bacterial membrane protein targets tested the MEMbrane protein Single shoT Amplification Recipe-MemStarleads to high production yields of target protein. The use of MemStar has facilitated structural studies of several transport proteins.

  • 2.
    Coincon, Mathieu
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dotson, David L.
    Winkelmann, Iven
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abdul-Hussein, Saba
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cameron, Alexander D.
    Beckstein, Oliver
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters2016In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 23, no 3, p. 248-255Article in journal (Refereed)
    Abstract [en]

    To fully understand the transport mechanism of Na+/H+ exchangers, it is necessary to clearly establish the global rearrangements required to facilitate ion translocation. Currently, two different transport models have been proposed. Some reports have suggested that structural isomerization is achieved through large elevator-like rearrangements similar to those seen in the structurally unrelated sodium-coupled glutamate-transporter homolog Glt(ph). Others have proposed that only small domain movements are required for ion exchange, and a conventional rocking-bundle model has been proposed instead. Here, to resolve these differences, we report atomic-resolution structures of the same Na+/H+ antiporter (NapA from Thermus thermophilus) in both outward- and inward-facing conformations. These data combined with cross-linking, molecular dynamics simulations and isothermal calorimetry suggest that Na+/H+ antiporters provide alternating access to the ion-binding site by using elevator-like structural transitions.

  • 3. Cotrim, Camila A.
    et al.
    Jarrott, Russell J.
    Martin, Jennifer L.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A structural overview of the zinc transporters in the cation diffusion facilitator family2019In: Acta Crystallographica Section D Structural Biology, ISSN 2059-7983, Vol. 75, p. 357-367Article, review/survey (Refereed)
    Abstract [en]

    The cation diffusion facilitators (CDFs) are a family of membrane-bound proteins that maintain cellular homeostasis of essential metal ions. In humans, the zinc-transporter CDF family members (ZnTs) play important roles in zinc homeostasis. They do this by facilitating zinc efflux from the cytoplasm to the extracellular space across the plasma membrane or into intracellular organelles. Several ZnTs have been implicated in human health owing to their association with type 2 diabetes and neurodegenerative diseases. Although the structure determination of CDF family members is not trivial, recent advances in membrane-protein structural biology have resulted in two structures of bacterial YiiPs and several structures of their soluble C-terminal domains. These data reveal new insights into the molecular mechanism of ZnT proteins, suggesting a unique rocking-bundle mechanism that provides alternating access to the metal-binding site.

  • 4.
    Drew, David
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Boudker, Olga
    Shared Molecular Mechanisms of Membrane Transporters2016In: Annual Review of Biochemistry, ISSN 0066-4154, E-ISSN 1545-4509, Vol. 85, p. 543-572Article, review/survey (Refereed)
    Abstract [en]

    The determination of the crystal structures of small-molecule transporters has shed light on the conformational changes that take place during structural isomerization from outward-to inward-facing states. Rather than using a simple rocking movement of two bundles around a central substrate-binding site, it has become clear that even the most simplistic transporters utilize rearrangements of nonrigid bodies. In the most dramatic cases, one bundle is fixed while the other, structurally divergent, bundle carries the substrate some 18 angstrom across the membrane, which in this review is termed an elevator alternating-access mechanism. Here, we compare and contrast rocker-switch, rocking-bundle, and elevator alternating-access mechanisms to highlight shared features and novel refinements to the basic alternating-access model.

  • 5. Gupta, Kallol
    et al.
    Donlan, Joseph A. C.
    Hopper, Jonathan T. S.
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Landreh, Michael
    Struwe, Weston B.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Baldwin, Andrew J.
    Stansfeld, Phillip J.
    Robinson, Carol V.
    The role of interfacial lipids in stabilizing membrane protein oligomers2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 541, no 7637, p. 421-424Article in journal (Refereed)
    Abstract [en]

    Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways(1) but is often difficult to define(2) or predict(3). Here we report the development of a mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125 alpha-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT(4), one of the proteins with the lowest oligomeric stability), we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET(5), another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na+/H+ antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of a-helical membrane proteins, including G-protein-coupled receptors.

  • 6.
    Hjelm, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Schlegel, Susan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Baumgarten, Thomas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Klepsch, Mirjam
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wickström, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Optimizing E. coli-Based Membrane Protein Production Using Lemo21(DE3) and GFP-Fusions2013In: Membrane Biogenesis: Methods and Protocols / [ed] Doron Rapaport, Johannes M. Herrmann, Totowa, USA: Humana Press, 2013, p. 381-400Chapter in book (Refereed)
    Abstract [en]

    Optimizing the conditions for the overexpression of membrane proteins in E. coli and their subsequent purification is usually a laborious and time-consuming process. Combining the Lemo21(DE3) strain, which conveniently allows to identify the optimal expression intensity of a membrane protein using only one strain, and membrane proteins C-terminally fused to Green Fluorescent Protein (GFP) greatly facilitates the production of high-quality membrane protein material for functional and structural studies.

  • 7. Landreh, Michael
    et al.
    Liko, Idlir
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Coincon, Mathieu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hopper, Jonathan T. S.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Robinson, Carol V.
    Controlling release, unfolding and dissociation of membrane protein complexes in the gas phase through collisional cooling2015In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 51, no 85, p. 15582-15584Article in journal (Refereed)
    Abstract [en]

    Mass spectrometry of intact membrane protein complexes requires removal of the detergent micelle by collisional activation. We demonstrate that the necessary energy can be obtained by adjusting the degree of collisional cooling in the ion source. This enables us to extend the energy regime for dissociation of membrane protein complexes.

  • 8. Landreh, Michael
    et al.
    Marklund, Erik G.
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Degiacomi, Matteo T.
    Coincon, Mathieu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gault, Joseph
    Gupta, Kallol
    Liko, Idlir
    Benesch, Justin L. P.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Robinson, Carol V.
    Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13993Article in journal (Refereed)
    Abstract [en]

    Na+/H+ antiporters are found in all kingdoms of life and exhibit catalysis rates that are among the fastest of all known secondary- active transporters. Here we combine ion mobility mass spectrometry and molecular dynamics simulations to study the conformational stability and lipid- binding properties of the Na+/H+ exchanger NapA from Thermus thermophilus and compare this to the prototypical antiporter NhaA from Escherichia coli and the human homologue NHA2. We find that NapA and NHA2, but not NhaA, form stable dimers and do not selectively retain membrane lipids. By comparing wild- type NapA with engineered variants, we show that the unfolding of the protein in the gas phase involves the disruption of inter- domain contacts. Lipids around the domain interface protect the native fold in the gas phase by mediating contacts between the mobile protein segments. We speculate that elevator- type antiporters such as NapA, and likely NHA2, use a subset of annular lipids as structural support to facilitate large- scale conformational changes within the membrane.

  • 9. Lee, Chiara
    et al.
    Kang, Hae Joo
    Hjelm, Anna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qureshi, Abdul Aziz
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Choudhury, Hassanul
    Beis, Konstantinos
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London, England.
    MemStar: A one-shot Escherichia coli-based approach for high-level bacterial membrane protein production2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 20, p. 3761-3769Article in journal (Refereed)
    Abstract [en]

    Optimising membrane protein production yields in Escherichia coli can be time- and resource-consuming. Here, we present a simple and effective Membrane protein Single shot amplification recipe: MemStar. This one-shot amplification recipe is based on the E. coli strain Lemo21(DE3), the PASM-5052 auto-induction medium and, contradictorily, an IPTG induction step. Using MemStar, production yields for most bacterial membrane proteins tested were improved to reach an average of 5 mg L-1 per OD600 unit, which is significantly higher than yields obtained with other common production strategies. With MemStar, we have been able to obtain new structural information for several transporters, including the sodium/proton antiporter NapA. (C) 2014 Federation of European Biochemical Societies.

  • 10. Lee, Chiara
    et al.
    Kang, Hae Joo
    von Ballmoos, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Newstead, Simon
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dotson, David L.
    Iwata, So
    Beckstein, Oliver
    Cameron, Alexander D.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London .
    A two-domain elevator mechanism for sodium/proton antiport2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, no 7468, p. 573-577Article in journal (Refereed)
    Abstract [en]

    Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets(2). The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli(1,3), for which both electron microscopy and crystal structures are available(4-6). NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein(1,4). Likemany Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur(7). The only reported NhaA crystal structure so far is of the low pH inactivated form(4). Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 angstrom resolution, solved from crystals grown at pH7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding(1,8,9) directly, a role supported hereby molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20 degrees against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second(3), Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.

  • 11. Lee, Chiara
    et al.
    Yashiro, Shoko
    Dotson, David L.
    Uzdavinys, Povilas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Iwata, So
    Sansom, Mark S. P.
    von Ballmoos, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Beckstein, Oliver
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London, England.
    Cameron, Alexander D.
    Crystal structure of the sodium-proton antiporter NhaA dimer and new mechanistic insights2014In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 144, no 6, p. 529-544Article in journal (Refereed)
    Abstract [en]

    Sodium-proton antiporters rapidly exchange protons and sodium ions across the membrane to regulate intracellular pH, cell volume, and sodium concentration. How ion binding and release is coupled to the conformational changes associated with transport is not clear. Here, we report a crystal form of the prototypical sodium-proton antiporter NhaA from Escherichia coli in which the protein is seen as a dimer. In this new structure, we observe a salt bridge between an essential aspartic acid (Asp163) and a conserved lysine (Lys300). An equivalent salt bridge is present in the homologous transporter NapA, but not in the only other known crystal structure of NhaA, which provides the foundation of most existing structural models of electrogenic sodium-proton antiport. Molecular dynamics simulations show that the stability of the salt bridge is weakened by sodium ions binding to Asp164 and the neighboring Asp163. This suggests that the transport mechanism involves Asp163 switching between forming a salt bridge with Lys300 and interacting with the sodium ion. pK(a) calculations suggest that Asp163 is highly unlikely to be protonated when involved in the salt bridge. As it has been previously suggested that Asp163 is one of the two residues through which proton transport occurs, these results have clear implications to the current mechanistic models of sodium-proton antiport in NhaA.

  • 12.
    Nji, Emmanuel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chatzikyriakidou, Yurie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Landreh, Michael
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    An engineered thermal-shift screen reveals specific lipid preferences of eukaryotic and prokaryotic membrane proteins2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4253Article in journal (Refereed)
    Abstract [en]

    Membrane bilayers are made up of a myriad of different lipids that regulate the functional activity, stability, and oligomerization of many membrane proteins. Despite their importance, screening the structural and functional impact of lipid-protein interactions to identify specific lipid requirements remains a major challenge. Here, we use the FSEC-TS assay to show cardiolipin-dependent stabilization of the dimeric sodium/proton antiporter NhaA, demonstrating its ability to detect specific protein-lipid interactions. Based on the principle of FSECTS, we then engineer a simple thermal-shift assay (GFP-TS), which facilitates the highthroughput screening of lipid-and ligand-interactions with membrane proteins. By comparing the thermostability of medically relevant eukaryotic membrane proteins and a selection of bacterial counterparts, we reveal that eukaryotic proteins appear to have evolved to be more dependent to the presence of specific lipids.

  • 13.
    Nji, Emmanuel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gulati, Ashutosh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qureshi, Abdul Aziz
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Coincon, Mathieu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structural basis for the delivery of activated sialic acid into Golgi for sialyation2019In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 26, no 6, p. 415-423Article in journal (Refereed)
    Abstract [en]

    The decoration of secretory glycoproteins and glycolipids with sialic acid is critical to many physiological and pathological processes. Sialyation is dependent on a continuous supply of sialic acid into Golgi organelles in the form of CMP-sialic acid. Translocation of CMP-sialic acid into Golgi is carried out by the CMP-sialic acid transporter (CST). Mutations in human CST are linked to glycosylation disorders, and CST is important for glycopathway engineering, as it is critical for sialyation efficiency of therapeutic glycoproteins. The mechanism of how CMP-sialic acid is recognized and translocated across Golgi membranes in exchange for CMP is poorly understood. Here we have determined the crystal structure of a Zea mays CST in complex with CMP. We conclude that the specificity of CST for CMP-sialic acid is established by the recognition of the nucleotide CMP to such an extent that they are mechanistically capable of both passive and coupled antiporter activity.

  • 14. Nomura, Norimichi
    et al.
    Verdon, Gregory
    Kang, Hae Joo
    Shimamura, Tatsuro
    Nomura, Yayoi
    Sonoda, Yo
    Hussien, Saba Abdul
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qureshi, Aziz Abdul
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Coincon, Mathieu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sato, Yumi
    Abe, Hitomi
    Nakada-Nakura, Yoshiko
    Hino, Tomoya
    Arakawa, Takatoshi
    Kusano-Arai, Osamu
    Iwanari, Hiroko
    Murata, Takeshi
    Kobayashi, Takuya
    Hamakubo, Takao
    Kasahara, Michihiro
    Iwata, So
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Imperial College London, UK.
    Structure and mechanism of the mammalian fructose transporter GLUT52015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7573, p. 397-+Article in journal (Refereed)
    Abstract [en]

    The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward-and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.

  • 15.
    Qureshi, Abdul Aziz
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Suades, Albert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Matsuoka, Rei
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brock, Joseph
    McComas, Sarah
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Claesson, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Delemotte, Lucie
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Malarial parasite transporter structure reveals the molecular basis for sugar importManuscript (preprint) (Other academic)
  • 16.
    Qureshi, Abdul Aziz
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Suades, Albert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    McComas, Sarah
    Delemotte, Lucie
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lipids shape the flat energetic landscape of the GLUT transporter cycleManuscript (preprint) (Other academic)
  • 17.
    Uzdavinys, Povilas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Coincon, Mathieu
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ndi, Mama
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Winkelmann, Iven
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Ballmoos, Christoph
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dissecting the proton transport pathway in electrogenic Na+/H+ antiporters2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 7, p. E1101-E1110Article in journal (Refereed)
    Abstract [en]

    Sodium/proton exchangers of the SLC9 family mediate the transport of protons in exchange for sodium to help regulate intracellular pH, sodium levels, and cell volume. In electrogenic Na+/H+ antiporters, it has been assumed that two ion-binding aspartate residues transport the two protons that are later exchanged for one sodium ion. However, here we show that we can switch the antiport activity of the bacterial Na+/H+ antiporter NapA from being electrogenic to electroneutral by the mutation of a single lysine residue (K305). Electroneutral lysine mutants show similar ion affinities when driven by Delta pH, but no longer respond to either an electrochemical potential (psi) or could generate one when driven by ion gradients. We further show that the exchange activity of the human Na+/H+ exchanger NHA2 (SLC9B2) is electroneutral, despite harboring the two conserved aspartic acid residues found in NapA and other bacterial homologues. Consistently, the equivalent residue to K305 in human NHA2 has been replaced with arginine, which is a mutation that makes NapA electroneutral. We conclude that a transmembrane embedded lysine residue is essential for electrogenic transport in Na+/H+ antiporters.

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