Crystal structure of the bacterial nucleoside transporter Tsx

Ye, Jiqing; Berg, Bert van den

doi:10.1038/sj.emboj.7600330

Cited by 99 publications

(93 citation statements)

References 47 publications

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“…Although PorB has previously been characterized as a nonselective channel, these electrostatics differ from those of other nonselective porins of known structure, which have consistent, intermediate charge (29,30). Because pore funnels with strongly opposing charges are observed in some substrate-specific channels (31,32), sugar binding was evaluated.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for solute transport, nucleotide regulation, and immunological recognition of Neisseria meningitidis PorB

Tanabe

Nimigean²,

Iverson³

2010

Proc. Natl. Acad. Sci. U.S.A.

110

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PorB is the second most prevalent outer membrane protein in Neisseria meningitidis. PorB is required for neisserial pathogenesis and can elicit a Toll-like receptor mediated host immune response. Here, the x-ray crystal structure of PorB has been determined to 2.3 Å resolution. Structural analysis and cocrystallization studies identify three putative solute translocation pathways through the channel pore: One pathway transports anions nonselectively, one transports cations nonselectively, and one facilitates the specific uptake of sugars. During infection, PorB likely binds host mitochondrial ATP, and cocrystallization with the ATP analog AMP-PNP suggests that binding of nucleotides regulates these translocation pathways both by partial occlusion of the pore and by restricting the motion of a putative voltage gating loop. PorB is located on the surface of N. meningitidis and can be recognized by receptors of the host innate immune system. Features of PorB suggest that Toll-like receptor mediated recognition outer membrane proteins may be initiated with a nonspecific electrostatic attraction.antibiotic resistance | innate immunity | outer membrane protein | porin | selectivity

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Section: Resultsmentioning

confidence: 99%

Structural basis for solute transport, nucleotide regulation, and immunological recognition of Neisseria meningitidis PorB

Tanabe

Nimigean²,

Iverson³

2010

Proc. Natl. Acad. Sci. U.S.A.

110

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“…A more recent study by Hazlett et al (57), however, has provided new evidence to suggest that Tp0453, a lipoprotein likely tethered to the inner leaflet of the treponemal outer membrane, has membrane-inserting amphipathic ␣-helices that transiently perturb the outer membrane, thereby culminating in enhanced outer membrane permeability. Inasmuch as T. pallidum does not possess orthologs of Tsx (15,44) or other porins or substrate-specific channels (4,15,58), it remains likely that the organism first avails itself of nucleosides by allowing them to traverse the outer membrane via some variation(s) of simple diffusion.…”

Section: Table 2 Oligonucleotide Primers Used For Rt-pcr In This Studymentioning

confidence: 99%

“…Based on earlier analyses, it was proposed that one or more of tp0319-tp0323 may encode members of an ABC transport system (43) and that Tp0319 may be a ligand-binding protein, but prior to our studies, there had been no indication that Tp0319 might represent an ABC transporter for nucleoside(s). In E. coli, nucleosides first traverse the outer membrane via Tsx, a 12-stranded ␤-barrel nucleoside-specific channel (44). Once in the periplasmic space, nucleosides then are transported across the cytoplasmic membrane by either of the high affinity transporters NupC or NupG, both of which are energized by the proton motive force (45).…”

Section: Table 2 Oligonucleotide Primers Used For Rt-pcr In This Studymentioning

confidence: 99%

The PnrA (Tp0319; TmpC) Lipoprotein Represents a New Family of Bacterial Purine Nucleoside Receptor Encoded within an ATP-binding Cassette (ABC)-like Operon in Treponema pallidum

Deka

Brautigam

Yang

et al. 2006

Journal of Biological Chemistry

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Treponema pallidum, the bacterial agent of syphilis, cannot be cultivated in vitro. This constraint has severely impeded the study of the membrane biology of this complex human pathogen. A structure-to-function approach thus was adopted as a means of discerning the likely function of Tp0319, a 35-kDa cytoplasmic membraneassociated lipoprotein of T. pallidum formerly designated as TmpC. A 1.7-Å crystal structure showed that recombinant Tp0319 (rTp0319) consists of two ␣/␤ domains, linked by three crossovers, with a deep cleft between them akin to ATP-binding cassette (ABC) receptors. In the cleft, a molecule of inosine was bound. Isothermal titration calorimetry demonstrated that rTp0319 specifically binds purine nucleosides (dissociation constant (K d ) ϳ10 ؊7 M). This predilection for purine nucleosides by rTp0319 is consistent with its likely role as a receptor component of a cytoplasmic membraneassociated transporter system. Reverse transcription-PCR analysis of RNA isolated from rabbit tissue-extracted T. pallidum additionally showed that tp0319 is transcriptionally linked to four other downstream open reading frames, thereby supporting the existence of an ABC-like operon (tp0319 -0323). We herein thus re-name tp0319 as purine nucleoside receptor A (pnrA), with its operonic partners tp0320 -0323 designated as pnrB-E, respectively. Our study not only infers that PnrA transports purine nucleosides essential for the survival of T. pallidum within its obligate human host, but to our knowledge, this is the first description of an ABC-type nucleoside transport system in any bacterium. PnrA has been grouped with a functionally uncharacterized protein family (HBG016869), thereby implying that other members of the family may have similar nucleoside-binding function(s).Treponema pallidum, the bacterial agent of syphilis, cannot be cultivated continuously in vitro (1). Historically, this constraint has severely hampered progress in understanding many features of this enigmatic pathogen. More specifically, key aspects of the membrane biology of T. pallidum, particularly as it pertains to the interaction of the pathogen with its human host, remain poorly defined (2-4). The initial discovery of membrane lipoproteins in T. pallidum (5, 6) spawned new avenues of investigation into treponemal membrane biology, inasmuch as in other bacteria, lipoproteins have importance as virulence factors, modular components of ATP-binding cassette (ABC) 3 transporters, receptors, protective immune targets, and proinflammatory agonists that elicit innate immune responses (7-14). In fact, genome analysis predicts that T. pallidum devotes as much as 3% of its genetic coding capacity to lipoproteins (15). However, to date, with one exception (9, 16), comparative sequence analyses have not been fruitful for predicting the functions of treponemal lipoproteins, and the inability to cultivate (and thus genetically manipulate) the organism has precluded using classical gene inactivation approaches (17) for investigating the functions of treponemal ...

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“…The importance of protein structure is underscored by the fact that amino acid mutations in a protein's primary sequence which destabilize its tertiary structure often result in disease [3]. , which binds to its target DNA sequence (red) by making sequence-specific contacts through the grooves in the DNA double-helix [4]; (b) Crystal structure of Tsx (PDB ID: 1tlz [5]), a nucleoside transporter protein, that transports nucleosides (red) by creating pores in the membrane through a β-barrel motif (shown here in blue); and (c) Crystal structure of keratin (PDB ID: 3tnu), a fibrous structural protein whose toughness can be attributed to the helical coiled-coil structure it adopts in its fibers [6].…”

Section: Introductionmentioning

confidence: 99%

Intrinsically Disordered Proteins: Where Computation Meets Experiment

2014

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Proteins are heteropolymers that play important roles in virtually every biological reaction. While many proteins have well-defined three-dimensional structures that are inextricably coupled to their function, intrinsically disordered proteins (IDPs) do not have a well-defined structure, and it is this lack of structure that facilitates their function. As many IDPs are involved in essential cellular processes, various diseases have been linked to their malfunction, thereby making them important drug targets. In this review we discuss methods for studying IDPs and provide examples of how computational methods can improve our understanding of IDPs. We focus on two intensely studied IDPs that have been implicated in very different pathologic pathways. The first, p53, has been linked to over 50% of human cancers, and the second, Amyloid-β (Aβ), forms neurotoxic aggregates in the brains of patients with Alzheimer's disease. We use these representative proteins to illustrate some of the challenges associated with studying IDPs and demonstrate how computational tools can be fruitfully applied to arrive at a more comprehensive understanding of these fascinating heteropolymers. OPEN ACCESSPolymers 2014, 6 2685

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Crystal structure of the bacterial nucleoside transporter Tsx

Cited by 99 publications

References 47 publications

Structural basis for solute transport, nucleotide regulation, and immunological recognition of Neisseria meningitidis PorB

Structural basis for solute transport, nucleotide regulation, and immunological recognition of Neisseria meningitidis PorB

The PnrA (Tp0319; TmpC) Lipoprotein Represents a New Family of Bacterial Purine Nucleoside Receptor Encoded within an ATP-binding Cassette (ABC)-like Operon in Treponema pallidum

Intrinsically Disordered Proteins: Where Computation Meets Experiment

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