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  • Journal article
    Wang S, Lin Y, Todorova N, Xu Y, Mazo M, Rana S, Leonardo V, Amdursky N, Spicer CD, Alexander BD, Edwards AA, Matthews SJ, Yarovsky I, Stevens MMet al., 2017,

    Facet-dependent interactions of islet amyloid polypeptide with gold nanoparti-cles: implications for fibril formation and peptide-induced lipid membrane dis-ruption

    , Chemistry of Materials, Vol: 29, ISSN: 1520-5002

    A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnos-tics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We uti-lized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmis-sion electron microscopy (TEM), and molecular dynamics (MD) simulations to systemati-cally elucidate the underlying mechanism of the IAPP−AuNP interactions. Because of the presence of a metal-binding sequence motif in the hydrophilic peptide domain, IAPP strongly interacts with the Au surface in both the monomeric and fibrillar states. Circular dichroism showed that AuNPs triggered the IAPP conformational transition from random coil to ordered structures (α-helix and β-sheet), and TEM imaging suggested the accelera-tion of IAPP fibrillation in the presence of AuNPs. MD simulations revealed that the IAPP−AuNP interactions were initiated by the N-terminal domain (IAPP residues 1−19), which subsequently induced a facet-dependent conformational change in IAPP. On a Au(111) surface, IAPP was unfolded and adsorbed directly onto the Au surface, while for the Au(100) surface, it interacted predominantly with the citrate adlayer and retained some helical conformation. The observed affinity of AuNPs for IAPP was further applied to reduce the level of peptide-induced lipid membrane disruption.

  • Journal article
    Larrouy-Maumus G, Layre E, Clark S, Prandi J, Rayner E, Lepore M, de Libero G, Williams A, Puzo G, Gilleron Met al., 2017,

    Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis

    , VACCINE, Vol: 35, Pages: 1395-1402, ISSN: 0264-410X
  • Conference paper
    Rouse SL, Hawthorne W, Berry J, Matthews Set al., 2017,

    Structural and Mechanistic Insights into Transport of Functional Amyloid Subunits across the Pseudomonas Outer Membrane

    , 61st Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 188A-188A, ISSN: 0006-3495
  • Journal article
    Eldridge MJG, Sanchez Garrido J, Hoben GF, Goddard PJ, Shenoy ARet al., 2017,

    The atypical ubiquitin E2 conjugase UBE2L3 is an indirect caspase-1 target and controls IL-1beta secretion by inflammasomes

    , Cell Reports, Vol: 18, Pages: 1285-1297, ISSN: 2211-1247

    Caspase-1 activation by inflammasome signalling scaffoldsinitiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-IL-1α into its mature form and directs its secretion, triggers pyroptosis and the release of non-substrate alarmins such as IL-1α and HMGB1. While somecaspase-1 substrates involved in these events are known, the identities and roles of non-proteolytic targets remain unknown. Here we report using unbiased proteomics that the UBE2L3 ubiquitin conjugase is an indirect target of caspase-1. Caspase-1, but not caspase-4, controlled pyroptosis-and ubiquitin-independent proteasomal degradation of UBE2L3 upon canonical and non-canonical inflammasome activation by sterile danger signals and bacterial infection. Mechanistically, UBE2L3 acted post-translationally to promote K48-ubiquitylation and turnover of pro-IL-1β and dampen mature-IL-1β production. UBE2L3 depletion increased pro-IL-1β levels and mature-IL-1βsecretion by inflammasomes. These findings on UBE2L3 as a molecular rheostat have implications for IL-1-driven pathology in hereditary fever syndromes, and autoinflammatory conditions associated with UBE2L3 polymorphisms.

  • Journal article
    Bosi E, Fondi M, Orlandini V, Perrin E, Maida I, de Pascale D, Tutino ML, Parrilli E, Lo Giudice A, Filloux A, Fani Ret al., 2017,

    The pangenome of (Antarctic) Pseudoalteromonas bacteria: evolutionary and functional insights

    , BMC Genomics, Vol: 18, ISSN: 1471-2164

    Background:Pseudoalteromonas is a genus of ubiquitous marine bacteria used as model organisms to study the biological mechanisms involved in the adaptation to cold conditions. A remarkable feature shared by these bacteria is their ability to produce secondary metabolites with a strong antimicrobial and antitumor activity. Despite their biotechnological relevance, representatives of this genus are still lacking (with few exceptions) an extensive genomic characterization, including features involved in the evolution of secondary metabolites production. Indeed, biotechnological applications would greatly benefit from such analysis.Results:Here, we analyzed the genomes of 38 strains belonging to different Pseudoalteromonas species and isolated from diverse ecological niches, including extreme ones (i.e. Antarctica). These sequences were used to reconstruct the largest Pseudoalteromonas pangenome computed so far, including also the two main groups of Pseudoalteromonas strains (pigmented and not pigmented strains). The downstream analyses were conducted to describe the genomic diversity, both at genus and group levels. This allowed highlighting a remarkable genomic heterogeneity, even for closely related strains. We drafted all the main evolutionary steps that led to the current structure and gene content of Pseudoalteromonas representatives. These, most likely, included an extensive genome reduction and a strong contribution of Horizontal Gene Transfer (HGT), which affected biotechnologically relevant gene sets and occurred in a strain-specific fashion. Furthermore, this study also identified the genomic determinants related to some of the most interesting features of the Pseudoalteromonas representatives, such as the production of secondary metabolites, the adaptation to cold temperatures and the resistance to abiotic compounds.Conclusions:This study poses the bases for a comprehensive understanding of the evolutionary trajectories followed in time by this peculiar bact

  • Journal article
    Pearson JS, Giogha C, Muhlen S, Nachbur U, Pham CLL, Zhang Y, Hildebrand JM, Oates CV, Lung TWF, Ingle D, Dagley LF, Bankovacki A, Petrie EJ, Schroeder GN, Crepin VF, Frankel G, Masters SL, Vince J, Murphy JM, Sunde M, Webb AI, Silke J, Hartland ELet al., 2017,

    EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation

    , NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276
  • Journal article
    Gunster R, Matthews SA, Holden DW, Thurston Tet al., 2017,

    SseK1 and SseK3 T3SS effectors inhibit NF-kB signalling and necroptotic cell death in Salmonella-infected macrophages

    , Infection and Immunity, Vol: 85, ISSN: 1098-5522

    Within host cells such as macrophages, Salmonella enterica translocates virulence (effector) proteins across its vacuolar membrane using the SPI-2 type III secretion system. Previously it has been shown that when expressed ectopically the effectors SseK1 and SseK3 inhibit TNFα-induced NF-κB activation. In this study we show that ectopically expressed SseK1, SseK2 and SseK3 suppressed TNFα-, but not TLR4-, or interleukin-induced NF-κB activation. Inhibition required a DXD motif, which in SseK1 and SseK3 is essential for protein Arginine-N-acetylglucosamine (GlcNAc)-ylation. During macrophage infection, SseK1 and SseK3 inhibited NF-κB activity in an additive manner. SseK3-mediated inhibition of NF-κB activation did not require the only known host-binding partner of this effector, the E3-ubiquitin ligase TRIM32. SseK proteins also inhibited TNFα-induced cell death during macrophage infection. Despite SseK1 and SseK3 inhibiting TNFα-induced apoptosis upon ectopic expression in HeLa cells, the percentage of infected macrophages undergoing apoptosis was SseK-independent. Instead, SseK proteins inhibited necroptotic cell death during macrophage infection. SseK1 and SseK3 caused GlcNAcylation of different proteins in infected macrophages suggesting that these effectors have distinct substrate specificities. Indeed, SseK1 caused the GlcNAcylation of the death domain containing proteins FADD and TRADD, whereas SseK3 expression resulted in weak GlcNAcylation of TRADD but not FADD. Additional, as yet unidentified substrates are likely to explain the additive phenotype of a Salmonella strain lacking both SseK1 and SseK3.

  • Journal article
    Bernal P, Allsopp LP, Filloux AAM, Llamas MAet al., 2017,

    The Pseudomonas putida T6SS is a plant warden against phytopathogens

    , The ISME Journal, Vol: 11, Pages: 972-987, ISSN: 1751-7362

    Bacterial type VI secretion systems (T6SSs) are molecular weapons designed to deliver toxic effectors into prey cells. These nanomachines play an important role in inter-bacterial competition and provide advantages to T6SS active strains in polymicrobial environments. Here we analyse the genome of the biocontrol agent Pseudomonas putida KT2440 and identify three T6SS gene clusters (K1-, K2- and K3-T6SS). Besides, ten T6SS effector/immunity pairs were found, including putative nucleases and pore-forming colicins. We show that the K1-T6SS is a potent antibacterial device which secretes a toxic Rhs-type effector Tke2. Remarkably, P. putida eradicates a broad range of bacteria in a K1-T6SS-dependent manner, including resilient phytopathogens which demonstrates that the T6SS is instrumental to empower P. putida to fight against competitors. Furthermore, we observed a drastically reduced necrosis on the leaves of Nicotiana benthamiana during co-infection with P. putida and Xanthomonas campestris. Such protection is dependent on the activity of the P. putida T6SS. Many routes have been explored to develop biocontrol agents capable of manipulating the microbial composition of the rhizosphere and phyllosphere. Here we unveil a novel mechanism for plant biocontrol which needs to be considered for the selection of plant wardens whose mission is to prevent phytopathogen infections.

  • Journal article
    Mesquita FS, Brito C, Mazon Moya MJ, Pinheiro JC, Mostowy S, Cabanes D, Sousa Set al., 2016,

    Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins

    , EMBO REPORTS, Vol: 18, Pages: 303-318, ISSN: 1469-221X
  • Journal article
    J√łnsson R, Liu B, Struve C, Yang Y, Jenssen H, Krogfelt K, Matthews SJet al., 2016,

    Structural and functional studies of Escherichia coli Aggregative Adherence Fimbriae (AAF/V) reveal a deficiency in extracellular matrix binding

    , BBA Protein and Proteomics, Vol: 1865, Pages: 304-311, ISSN: 1570-9639

    Enteroaggregative Escherichia coli (EAEC) is an emerging cause of acute and persistent diarrhea worldwide. The pathogenesis of different EAEC stains is complicated, however, the early essential step begins with attachment of EAEC to intestinal mucosa via aggregative adherence fimbriae (AAFs). Currently, five different variants have been identified, which all share a degree of similarity in the gene organization of their operons and sequences. Here, we report the solution structure of Agg5A from the AAF/V variant. While preserving the major structural features shared by all AAF members, only Agg5A possesses an inserted helix at the beginning of the donor strand, which together with altered surface electrostatics, renders the protein unable to interact with fibronectin. Hence, here we characterize the first AAF variant with a binding mode that varies from previously described AAFs

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