161 research outputs found
Characteristics of the first protein tyrosine phosphatase with phytase activity from a soil metagenome
No full text Protein tyrosine phosphatases (PTPs) fulfil multiple key regulatory functions. Within the group of PTPs, the atypical lipid phosphatases (ALPs) are known for their role as virulence factors associated with human pathogens. Another group of PTPs, which is capable of using inositol-hexakisphosphate (InsP 6 ) as substrate, are known as phytases. Phytases play major roles in the environmental phosphorus cycle, biotechnology, and pathogenesis. So far, all functionally characterized PTPs, including ALPs and PTP-phytases, have been derived exclusively from isolated microorganisms. In this study, screening of a soil-derived metagenomic library resulted in identification of a gene (pho16B), encoding a PTP, which shares structural characteristics with the ALPs. In addition, the characterization of the gene product (Pho16B) revealed the capability of the protein to use InsP 6 as substrate, and the potential of soil as a source of phytases with so far unknown characteristics. Thus, Pho16B represents the first functional environmentally derived PTP-phytase. The enzyme has a molecular mass of 38 kDa. The enzyme is promiscuous, showing highest activity and affinity toward naphthyl phosphate (K m 0.966 mM). Pho16B contains the HCXXGKDR[TA]G submotif of PTP-ALPs, and it is structurally related to PtpB of Mycobacterium tuberculosis. This study demonstrates the presence and functionality of an environmental gene codifying a PTP-phytase homologous to enzymes closely associated to bacterial pathogenicity. </p
Identification and functional analysis of a novel oculocerebrorenal syndrome of Lowe (OCRL) gene variant in two pedigrees with varying phenotypes including isolated congenital cataract
No full textPurpose: To identify the genetic variation in two unrelated probands with congenital cataract and to perform functional analysis of the detected variants. Methods: Clinical examination and phenotyping, segregation, and functional analysis were performed for the two studied pedigrees. Results: A novel OCRL gene variant (c.1964A>T, p. (Asp655Val)) was identified. This variant causes defects in OCRL protein folding and mislocalization to the cytoplasm. In addition, the variant’s location close to the Rab binding site is likely to be associated with membrane targeting abnormalities. Conclusions: The results highlight the importance of early genetic diagnosis in infants with congenital cataract and show that mutations in the OCRL gene can present as apparently isolated congenital cataract
The TriTryp Phosphatome: analysis of the protein phosphatase catalytic domains
No full textAbstract Background The genomes of the three parasitic protozoa Trypanosoma cruzi, Trypanosoma brucei and Leishmania major are the main subject of this study. These parasites are responsible for devastating human diseases known as Chagas disease, African sleeping sickness and cutaneous Leishmaniasis, respectively, that affect millions of people in the developing world. The prevalence of these neglected diseases results from a combination of poverty, inadequate prevention and difficult treatment. Protein phosphorylation is an important mechanism of controlling the development of these kinetoplastids. With the aim to further our knowledge of the biology of these organisms we present a characterisation of the phosphatase complement (phosphatome) of the three parasites. Results An ontology-based scan of the three genomes was used to identify 86 phosphatase catalytic domains in T. cruzi, 78 in T. brucei, and 88 in L. major. We found interesting differences with other eukaryotic genomes, such as the low proportion of tyrosine phosphatases and the expansion of the serine/threonine phosphatase family. Additionally, a large number of atypical protein phosphatases were identified in these species, representing more than one third of the total phosphatase complement. Most of the atypical phosphatases belong to the dual-specificity phosphatase (DSP) family and show considerable divergence from classic DSPs in both the domain organisation and sequence features. Conclusion The analysis of the phosphatome of the three kinetoplastids indicates that they possess orthologues to many of the phosphatases reported in other eukaryotes, including humans. However, novel domain architectures and unusual combinations of accessory domains, suggest distinct functional roles for several of the kinetoplastid phosphatases, which await further experimental exploration. These distinct traits may be exploited in the selection of suitable new targets for drug development to prevent transmission and spread of the diseases, taking advantage of the already extensive knowledge on protein phosphatase inhibitors.</p
Virtual epitexts in the dissemination of children’s books: Toward an analytical model for author websites
No full textSummary: Author websites form a corpus of epitexts (Lluch et al., 2015) that in the context of the knowledge society need to be studied to identify how authors present and disseminate their books and promote reading on the social web. The aim of the research is to identify the key aspects for an analytical model for the websites of authors of children’s books. To this end, from within the portal Picturebook Makers, we selected the websites of three authors: Oliver Jeffers, Isol and Manuel Marsol. We analysed these websites using a selection of three of parameters. The results show that this virtual public epitext is in some cases an adaptation of analogue models of dissemination, while in others, such as the site of Jeffers, it leans toward a transmedia discourse in which the book-trailer is an essential tool for promoting the work. Keywords: Virtual Public Epitext, author websites, picture book, book-trailer, transmedi
8599105 BSc (Hons) Pharmacology & Physiology Structural Analysis of Protein Tyrosine Phosphatases
No full textHyper-adhesion: a unique property of desmosomes.
No full textHyper-adhesion is a unique, strongly adhesive form of desmosomal adhesion that functions to maintain tissue integrity. In this short review, we define hyper-adhesion, summarise the evidence for it in culture and in vivo, discuss its role in development, wound healing, and skin disease, and speculate about its molecular and cellular basis
Molecular structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with the minor groove binding drug netropsin
No full textThe molecular structure of the complex between the minor groove binding drug netropsin and the dodecamer d(CGCAAATTTGCG) has been solved and refined by X-ray diffraction analysis to an R-factor of 19.8% and 2.2-Å resolution. The drug lies in the narrow minor groove of the B-DNA fragment, covering five of the six A·T base pairs (from A5·T20 to T9·A16). The long six A·T base pair tract allows the drug to bind in a position that optimizes its contacts with the DNA, establishing hydrogen bonds with O2 of thymines and N3 of adenines. The DNA molecule shows a high propeller twist only at the A6·T19 step of the A-tract. Two three-centered hydrogen bonds are observed in the major groove at half of the A-tract. © 1993 American Chemical Society
Virtual epitexts in the dissemination of children's books: Toward an analytical model for author websites
No full textAuthor websites form a corpus of epitexts (Lluch et al., 2015) that in the context of the knowledge society need to be studied to identify how authors present and disseminate their books and promote reading on the social web. The aim of the research is to identify the key aspects for an analytical model for the websites of authors of children’s books. To this end, from within the portal Picturebook Makers, we selected the websites of three authors: Oliver Jeffers, Isol and Manuel Marsol. We analysed these websites using a selection of three of parameters. The results show that this virtual public epitext is in some cases an adaptation of analogue models of dissemination, while in others, such as the site of Jeffers, it leans toward a transmedia discourse in which the book-trailer is an essential tool for promoting the work
Hydrogen bond geometry in DNA-minor groove binding drug complexes
No full textThe geometry of the hydrogen bonding interaction between DNA and minor-groove binding drugs has been analyzed from a sample of 22 crystal structures of DNA-drug complexes, retrieved from the Nucleic Acid Database. Seventy-seven interactions between the drugs and acceptor groups in the nucleotide bases can be classified as hydrogen bonds. Their geometry departs significantly from linearity since, in most instances, the interactions can be described as three-center or multiple hydrogen bonds. Results also show that there is no preference for hydrogen bonds involving positively charged groups in the drugs. Relationships between hydrogen bond geometry and positioning of the drug along the minor groove are also discussed. The information presented may be useful in the design of new specific minor groove binding drugs
A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis
No full textThe kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screening pipeline, to identify a ligand cluster distribution that is unique to this subfamily of PTPs. Several clusters map onto KIM-PTP specific sequence motifs in contrast to the cluster distribution obtained for PTP1B, a classic PTP that mapped to general PTP motifs. Importantly, the ligand clusters coincide with previously reported functional and substrate binding sites in KIM-PTPs. Assessment of the KIM-PTP specific clusters, using ligand efficiency index (LEI) plots generated by the VSpipe, ascertained that the binders in these clusters reside in a more drug like chemical-biological space than those at the active site. LEI analysis showed differences between clusters across all KIM-PTPs, highlighting a distinct and specific profile for each phosphatase. The most druggable cluster sites are unexplored allosteric functional sites unique to each target. Exploiting these sites may facilitate the delivery of inhibitors of improved drug-like properties with selectivity amongst the KIM-PTPs and over other classical PTPs
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