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The Proline-Rich Domain of Tonb Possesses an Extended Polyproline II-Like Conformation of Sufficient Length to Span the Periplasm of Gram-Negative Bacteria

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The Proline-Rich Domain of Tonb Possesses an Extended Polyproline II-Like Conformation of Sufficient Length to Span the Periplasm of Gram-Negative Bacteria The proline-rich domain of TonB possesses an extended polyproline II-like conformation of sufficient length to span the periplasm of Gram-negative bacteria Silvia Domingo Kohler,1 Annemarie Weber,2 S. Peter Howard,3 Wolfram Welte,2* and Malte Drescher1* 'Department of Chemistry, University of Konstanz, Konstanz 78457, Germany 2Department of Biology, University of Konstanz, Konstanz 78457, Germany 3Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5 DOl: 10.1 002/pro.345 Abstract: TonB from Escherichia coli and its homologues are critical for the uptake of siderophores through the outer membrane of Gram-negative bacteria using chemiosmotic energy. When different models for the mechanism of TonB mediated energy transfer from the inner to the outer membrane are discussed, one of the key questions is whether TonB spans the periplasm. In this article, we use long range distance measurements by spin-label pulsed EPR (Double Electron-Electron Resonance, DEER) and CD spectroscopy to show that the proline-rich segment of TonB exists in a PPII-like conformation. The result implies that the proline-rich segment of TonB possesses a length of more than 15 nm, sufficient to span the periplasm of Gram-negative bacteria. Keywords: TonB; outer membrane; active transport; EPR; DEER; polyproline 11 Introduction ing of phages such as T1 (eponymous) and <jlBO.2 The TonB from Escherichia coli and its homologues are TonB system is also critical for uptake of bacterial critical for the uptake of siderophores and a number toxins like colicin la and B3 and certain antibiotics 4 of other nutrients through the outer membrane of (albomycin, rifamycin, and microcin 25 ). In complex Gram-negative bacteria,l and in E. coli for the dock- with the cytoplasmic membrane proteins ExbB and ExbD, and dependent on the proton motive force, TonB serves a large class of "To nB-dependent" outer membrane receptors, each responsible for the uptake of specific cargo molecules, including iron complexed Silvia Oomingo Kohler and Annemarie Weber contributed by siderophores, heme,5 transferrin6 and lactoferrin, equally to this work. cobalt as cyanocobalamin, nickel, copper, thiamine, Grant sponsor: Oeutsche Forschungsgemeinschaft; Grant and carbohydrates.7 In the cell, these receptors out­ number: OR 743/2-1; Grant sponsor: Natural Sciences and number TonB. For the FepA receptor and TonB, for Engineering Research Council of Canada. example, a molar ratio of 12.5 has been estimated.8 'Correspondence to: Wolfram Welte, University of Konstanz, This suggests that the transport mechanism involves UniversitatsstraBe 10, 78457 Konstanz, Germany. E-mail: [email protected] or Malte Orescher, University of a mobile sampling mechanism in which each TonB Konstanz, UniversitatsstraBe 10, 78457 Konstanz, Germany. complex interacts transiently with many different E-mail: [email protected] receptors, recognizing those that are ligand loaded 625 and in some way transducing energy derived from In one model, TonB adopts an energy-rich con­ the proton motive force to them to effectuate formation through interaction with ExbBlExbD and transport. the proton motive force. This "loaded-spring" dissoci­ Within an N-terminal stretch of 32 residues (in ates from the cytoplasmic membrane, diffuses across E. coli) a hydrophobic segment anchors TonB in the the periplasmic space, binds to cargo-loaded recep­ cytoplasmic membrane (CM). This is followed by a tors and discharges its energy so that by means of proline-rich segment of ~100 residues that includes an unspecified mechanism the translocation of the a stretch of 68 residues in which more than 1 in ev­ cargo is effected ("shuttle model,,).22 In another ery 3 residues is a proline. A globular domain with model, TonB molecules, which are anchored in the affinity for TonB-dependent receptors forms the C­ CM but touch a loaded receptor on the periplasmic terminus of the protein. ExbB and ExbD, which ex­ side of the outer membrane, dimerize by means of hibit distant homology with components of the flag­ their C-terminal domain. ExbB and ExbD by means ellar motor/) appear to form a complex with of the proton motive force rotate the two TonB mole­ lO ll TonB. • Suppressor mutation analysis has sug­ cules. This torque leads to a twisting of the two gested that ExbB interacts with TonB through the TonB molecules pulling the C-terminal domains and transmembrane domain 12 while an NMR study sug­ the attached N-terminus of the receptor cork domain gested that ExbD interacts weakly with the periplas­ away from the outer membrane into the periplasmic mic domain. 13 space, thus unfolding the cork entirely or partially The crystal structures of several TonB-depend­ and abolishing the cargo binding site as well as cre­ ent receptors show a common architecture. 22- ating the exit channel ("propeller model,,).23 Gum­ stranded p-barrels span the outer membrane, with bart et al. 24 have studied the feasibility of partial the lumen filled almost completely by a cork domain unfolding or removal of the cork domain by a force formed by the N-terminal part of the receptor poly­ pulling at the C-terminal TonB perpendicular to the peptide. This leaves two pockets at the extracellular membrane into the periplasm by a molecular dy­ and the periplasmic openings of the p-barrel. Prior namics simulation. to TonB-mediated energy transduction, the cargo In accord with the shuttle model, the N-termi­ molecule is bound to a high-affinity site at the bot­ nal domain of TonB, which would be in the cyto­ tom of the extracellular pocket. Binding involves res­ plasm if it remained in the CM, could be labeled idues from the cork, the barrel and from the charac­ with a reagent impermeable to the cytoplasmic teristic long loops connecting p-strands of the barrel membrane, and only when it was functional in side­ on the extracellular side, which in some cases rophore transport.25 On the other hand, a study by enclose the binding site like petals. 14 The binding af­ Kaserer et al. 26 using TonB fusions is at odds with finity is typically in the nanomolar range, and bind­ the dissociation of TonB from the CM. For the pro­ ing occurs whether or not the cell has a functional peller model, the strongest support for the genera­ TonB system, indicating that energy transduction tion of a rotational torque stems from the homology through the TonB-receptor complex is required to between the ExbB and ExbD and the MotA and dissociate the cargo molecule from the binding site MotB proteins of the flagellar motor. However, no and to open an exit channel for its passage through evidence has been provided that TonB actually the barrel and into the periplasm. rotates and the observed 1:1 stochiometry of TonB Because TonB had been found critical for energy and receptor in the structure of the complex is not transduction from the cytoplasmic membrane to the in accord with this model without modifications. receptors, it was consistent that complexes of recep­ Thus far, differentiating between the shuttle tors with TonB were found to be stabilized upon and propeller models is not possible, in spite of the binding of cargo molecules. 15, 16 It was also in accord large amount of information about protein-protein with the observation of conformational transitions in interactions in the TonB energy transduction sys­ the structure of some receptors on the periplasmic tem. One item of information which could address 17 1H side after binding of cargo molecules. • Crystal the feasibility of the models, however, would be and NMR structures of the C-terminal globular do­ knowledge of the physical length of TonB. The width 15 19 main of TonB alone . and in complex with outer of the periplasm is estimated to be 15-20 nm,27 so 20 membrane receptors ,21 have been reported. In the TonB should match this length in order to be able to complexes the domain was in contact with the so­ deliver torque that is generated in the CM to a re­ called TonB-box of the receptors, a conserved stretch ceptor in the outer membrane. TonB and its homo­ of ~7 amino acids near the periplasmic N-terminal logues share a central proline-rich segment of 68 end of the cork domain. residues of which 24 are prolines. Moreover, in its Models have been proposed as to how TonB N-terminal half acidic residues but no basic residues might transduce electrochemical energy to the recep­ are abundant whereas in its C-terminal half this tors so as to effect cargo translocation from the re­ pattern is reversed. Short distance information from 28 ceptor binding site to the periplasm. NMR studies ,29 have already suggested that TonB 626 adopts an extended structure allowing it to span the estimated 20 nm width of the periplasmic space. The -- Ton8 59/69 1,0 anomalous migration in SDS-PAGE indicates rigid­ --Ton8 59/76 --Ton8 69176 ity and elongation as well. ~ o The high content of pro­ _. __. Ton8 69/84 c: line and the aqueous environment suggests that a o --Ton888/106 polyproline helix II (PPlI) would be a possible con­ S 0,8 --Ton8106/120 formation, that is a left-handed helix with an axial ~ translation of 0.31 nm per residue, rather than a I right-handed polyproline I helix (PP!) with an axial is 0,6 translation of 0.19 nm per residue. Experiments showed that the PPII conformation is maintained in proline-rich polypeptides up to a certain content of u other residues.: ,:l2 The dihedral angles of a PPII 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 conformation (cp = - 75", \~ = 145°, W = 180") resem­ t [)Is} ble those of an antiparallel ~-sheet.
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