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  • 1
    Online Resource
    Online Resource
    C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 28 ( 2014-07-15), p. 10155-10160
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 28 ( 2014-07-15), p. 10155-10160
    Abstract: Fibrillin microfibrils are 10–12 nm diameter, extracellular matrix assemblies that provide dynamic tissues of metazoan species with many of their biomechanical properties as well as sequestering growth factors and cytokines. Assembly of fibrillin monomers into microfibrils is thought to occur at the cell surface, with initial steps including proprotein processing, multimerization driven by the C terminus, and the head-to-tail alignment of adjacent molecules. At present the mechanisms that regulate microfibril assembly are still to be elucidated. We have used structure-informed protein engineering to create a recombinant, GFP-tagged version of fibrillin-1 (GFP-Fbn) to study this process. Using HEK293T cells transiently transfected with GFP-Fbn constructs, we show that ( i ) the C-terminal propeptide is an essential requirement for the secretion of full-length fibrillin-1 from cells; ( ii ) failure to cleave off the C-terminal propeptide blocks the assembly of fibrillin-1 into microfibrils produced by dermal fibroblasts; and ( iii ) the requirement of the propeptide for secretion is linked to the presence of domains cbEGF41-43, because either deletion or exchange of domains in this region leads to cellular retention. Collectively, these data suggest a mechanism in which the propeptide blocks a key site at the C terminus to prevent premature microfibril assembly.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1401697111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Effects of proline cis-trans isomerization on TB domain secondary structure
    Wiley ; 1998
    In:  Protein Science Vol. 7, No. 10 ( 1998-10), p. 2127-2135
    Details
    In: Protein Science, Wiley, Vol. 7, No. 10 ( 1998-10), p. 2127-2135
    Type of Medium: Online Resource
    ISSN: 0961-8368 , 1469-896X
    URL: Issue
    URL: Article
    DOI: 10.1002/pro.v7:10
    DOI: 10.1002/pro.5560071009
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 1998
    detail.hit.zdb_id: 2000025-X
    SSG: 12
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  • 3
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    Online Resource
    New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies
    Portland Press Ltd. ; 2016
    In:  Biochemical Journal Vol. 473, No. 7 ( 2016-04-01), p. 827-838
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 473, No. 7 ( 2016-04-01), p. 827-838
    Abstract: The 10–12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10–12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10–12 nm diameter microfibril and perform such diverse roles.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20151108
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2016
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Fringe-mediated extension of O -linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 20 ( 2014-05-20), p. 7290-7295
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 20 ( 2014-05-20), p. 7290-7295
    Abstract: The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11–13) of human Notch1 (hN1) with O -fucose and O -glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe-catalyzed addition of GlcNAc to the O -fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11–13 of hN1 modified with either the O -fucose monosaccharide or the GlcNAc–fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch–Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1319683111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Two novel protein O -glucosyltransferases that modify sites distinct from POGLUT1 and affect Notch trafficking and signaling
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 36 ( 2018-09-04)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 36 ( 2018-09-04)
    Abstract: The Notch-signaling pathway is normally activated by Notch–ligand interactions. A recent structural analysis suggested that a novel O -linked hexose modification on serine 435 of the mammalian NOTCH1 core ligand-binding domain lies at the interface with its ligands. This serine occurs between conserved cysteines 3 and 4 of Epidermal Growth Factor-like (EGF) repeat 11 of NOTCH1, a site distinct from those modified by protein O -glucosyltransferase 1 (POGLUT1), suggesting that a different enzyme is responsible. Here, we identify two novel protein O -glucosyltransferases, POGLUT2 and POGLUT3 (formerly KDELC1 and KDELC2, respectively), which transfer O -glucose ( O -Glc) from UDP-Glc to serine 435. Mass spectrometric analysis of NOTCH1 produced in HEK293T cells lacking POGLUT2 , POGLUT3 , or both genes showed that either POGLUT2 or POGLUT3 can add this novel O -Glc modification. EGF11 of NOTCH2 does not have a serine residue in the same location for this O -glucosylation, but EGF10 of NOTCH3 (homologous to EGF11 in NOTCH1 and -2) is also modified at the same position. Comparison of the sites suggests a consensus sequence for modification. In vitro assays with POGLUT2 and POGLUT3 showed that both enzymes modified only properly folded EGF repeats and displayed distinct acceptor specificities toward NOTCH1 EGF11 and NOTCH3 EGF10. Mutation of the O -Glc modification site on EGF11 (serine 435) in combination with sensitizing O -fucose mutations in EGF8 or EGF12 affected cell-surface presentation of NOTCH1 or reduced activation of NOTCH1 by Delta-like1, respectively. This study identifies a previously undescribed mechanism for fine-tuning the Notch-signaling pathway in mammals.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1804005115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Marfan syndrome caused by a mutation in FBN1 that gives rise to cryptic splicing and a 33 nucleotide insertion in the coding sequence
    Springer Science and Business Media LLC ; 2001
    In:  Human Genetics Vol. 109, No. 4 ( 2001-10), p. 416-420
    Details
    In: Human Genetics, Springer Science and Business Media LLC, Vol. 109, No. 4 ( 2001-10), p. 416-420
    Type of Medium: Online Resource
    ISSN: 0340-6717 , 1432-1203
    URL: Article
    DOI: 10.1007/s004390100573
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2001
    detail.hit.zdb_id: 1459188-1
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands
    EMBO ; 2017
    In:  The EMBO Journal Vol. 36, No. 15 ( 2017-08), p. 2204-2215
    Details
    In: The EMBO Journal, EMBO, Vol. 36, No. 15 ( 2017-08), p. 2204-2215
    Abstract: image Notch ligands possess variable lipid‐binding domains that mediate interaction with membranes of diverse lipid composition. A complex formation between Notch ligands, membrane lipids and Notch is required for efficient Notch signalling, and is disrupted in Jagged1 mutations associated with extrahepatic biliary atresia. New crystal structures for human Notch ligands Jagged2 and Delta‐like4 show variation in the ligand C2 domain lipid‐binding region, which is reflected by their binding preferences to liposomes of different compositions. Liposomes show enhanced binding to most ligands in the presence of Notch, suggesting a crosstalk between lipid and Notch binding. Selective loss of membrane binding appears to underlie defective Notch activation associated with a subset of Jagged1 C2 domain disease‐causing variants. The data suggest an important role for membrane binding in fine‐tuning the Notch signal in specific physiological contexts.
    Type of Medium: Online Resource
    ISSN: 0261-4189 , 1460-2075
    URL: Article
    DOI: 10.15252/embj.201796632
    RVK:
    WA 15000
    Language: English
    Publisher: EMBO
    Publication Date: 2017
    detail.hit.zdb_id: 1467419-1
    detail.hit.zdb_id: 586044-1
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Somatic mutant clones colonize the human esophagus with age
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6417 ( 2018-11-23), p. 911-917
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6417 ( 2018-11-23), p. 911-917
    Abstract: The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aau3879
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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