ORCID Profile
0000-0001-7297-7708
Current Organisation
University of Oxford
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Publisher: Wiley
Date: 05-02-2015
DOI: 10.1002/PROT.24758
Abstract: The biosynthesis of the glycopeptide antibiotics, of which teicoplanin and vancomycin are representative members, relies on the combination of non-ribosomal peptide synthesis and modification of the peptide by cytochrome P450 (Oxy) enzymes while the peptide remains bound to the peptide synthesis machinery. We have structurally characterized the final peptidyl carrier protein domain of the teicoplanin non-ribosomal peptide synthetase machinery: this domain is believed to mediate the interactions with tailoring Oxy enzymes in addition to its function as a shuttle for intermediates between multiple non-ribosomal peptide synthetase domains. Using solution state NMR, we have determined structures of this PCP domain in two states, the apo and the post-translationally modified holo state, both of which conform to a four-helix bundle assembly. The structures exhibit the same general fold as the majority of known carrier protein structures, in spite of the complex biosynthetic role that PCP domains from the final non-ribosomal peptide synthetase module must play in glycopeptide antibiotic biosynthesis. These structures thus support the hypothesis that it is subtle rearrangements, rather than dramatic conformational changes, which govern carrier protein interactions and selectivity during non-ribosomal peptide synthesis.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2013
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 04-2005
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
Publisher: Springer Science and Business Media LLC
Date: 11-03-2002
DOI: 10.1038/NSB768
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JMB.2010.06.039
Abstract: FBLN5 encodes fibulin-5, an extracellular matrix calcium-binding glycoprotein that is essential for elastic fibre formation. FBLN5 mutations are associated with two distinct human diseases, age-related macular degeneration (AMD) and cutis laxa (CL), but the biochemical basis for the pathogenic effects of these mutations is poorly understood. Two missense mutations found in AMD patients (I169T and G267S) and two missense mutations found in CL patients (G202R and S227P) were analysed in a native-like context in recombinant fibulin-5 fragments. Limited proteolysis, NMR spectroscopy and chromophoric calcium chelation experiments showed that the G267S and S227P substitutions cause long-range structural effects consistent with protein misfolding. Cellular studies using fibroblast cells further demonstrated that these recombinant forms of mutant fibulin-5 were not present in the extracellular medium, consistent with retention. In contrast, no significant effects of I169T and G202R substitutions on protein fold and secretion were identified. These data establish protein misfolding as a causative basis for the effects of G267S and S227P substitutions in AMD and CL, respectively, and raise the possibility that the I169T and G202R substitutions may be polymorphisms or may increase susceptibility to disease.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2008
DOI: 10.1038/NSMB.1457
Publisher: Elsevier BV
Date: 10-2013
Publisher: Elsevier BV
Date: 12-2004
Publisher: Elsevier BV
Date: 05-2009
Publisher: Elsevier BV
Date: 05-2002
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2009
End Date: 2011
Funder: Wellcome Trust
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