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  • 1
    Online Resource
    Online Resource
    GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 3 ( 2017-01-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 3 ( 2017-01-17)
    Abstract: The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6 −/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1614926114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    A single intact ATPase site of the ABC transporter BtuCD drives 5% transport activity yet supports full in vivo vitamin B 12 utilization
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 14 ( 2013-04-02), p. 5434-5439
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 14 ( 2013-04-02), p. 5434-5439
    Abstract: In all kingdoms of life, ATP binding cassette (ABC) transporters are essential to many cellular functions. In this large superfamily of proteins, two catalytic sites hydrolyze ATP to power uphill substrate translocation. A central question in the field concerns the relationship between the two ATPase catalytic sites: Are the sites independent of one another? Are both needed for function? Do they function cooperatively? These issues have been resolved for type I ABC transporters but never for a type II ABC transporter. The many mechanistic differences between type I and type II ABC transporters raise the question whether in respect to ATP hydrolysis the two subtypes are similar or different. We have addressed this question by studying the Escherichia coli vitamin B 12 type II ABC transporter BtuCD. We have constructed and purified a series of BtuCD variants where both, one, or none of the ATPase sites were rendered inactive by mutation. We find that, in a membrane environment, the ATPase sites of BtuCD are highly cooperative with a Hill coefficient of 2. We also find that, when one of the ATPase sites is inactive, ATP hydrolysis and vitamin B 12 transport by BtuCD is reduced by 95%. These exact features are also shared by the archetypical type I maltose ABC transporter. Remarkably, mutants that have lost 95% of their ATPase and transport capabilities still retain the ability to fully use vitamin B 12 in vivo. The results demonstrate that, despite the many differences between type I and type II ABC transporters, the fundamental mechanism of ATP hydrolysis remains conserved.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1209644110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Structural elements responsible for conversion of streptavidin to a pseudoenzyme
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 16 ( 2004-04-20), p. 5916-5921
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 16 ( 2004-04-20), p. 5916-5921
    Abstract: Avidin enhances the hydrolysis of biotinyl p -nitrophenyl ester (BNP) under mild alkaline conditions, whereas streptavidin prevents hydrolysis of BNP up to pH 12. Recently, we imposed hydrolytic activity on streptavidin by rational mutagenesis, based on the molecular elements responsible for the hydrolysis by avidin. Three mutants were designed, whereby the desired features, the distinctive L124R point mutation (M1), the L3,4 loop replacement (M2), and the combined mutation (M3), were transferred from avidin to streptavidin. The crystal structures of the mutants, in complex with biotinyl p -nitroanilide (BNA), the stable amide analogue of BNP, were determined. The results demonstrate that the point mutation alone has little effect on hydrolysis, and BNA exhibits a conformation similar to that of streptavidin. Substitution of a lengthier L3,4 loop (from avidin to streptavidin), resulted in an open conformation, thus exposing the ligand to solvent. Moreover, the amide bond of BNA was flipped relative to that of the streptavidin and M1 complexes, thus deflecting the nitro group toward Lys-121. Consequently, the leaving group potential of the nitrophenyl group of BNP is increased, and M2 hydrolyzes BNP at pH values 〉 8.5. To better emulate the hydrolytic potential of avidin, M3 was required. The combination of loop replacement and point mutation served to further increase the leaving group potential by interaction of the nitro group with Arg-124 and Lys-121. The information derived from this study may provide insight into the design of enzymes and transfer of desired properties among homologous proteins.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0308541101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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