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8. Novel numerical method for parameterising fretting contacts

Author

Wade, A, Copley, R, Alsheikh Omar, A, Clarke, B, Liskiewicz, T, Bryant, M, Wade, A, Copley, R, Alsheikh Omar, A, Clarke, B, Liskiewicz, T, and Bryant, M

Abstract

Fretting regime transition is traditionally achieved by qualitative assessment of the fretting loops (tangential force, vs tangential displacement ) and material response. Other studies used parameters in which thresholds are theoretically determined to exceed friction at the contact for regime transition identification. This study successfully developed a flexible loop analysis method based on simple vector principles that is able to quantify and characterise its constituent parts. In terms of fretting contact analysis the loop analysis method provided a complementary method of regime transition identification to those based on theoretically overcoming friction at the contact, with strong agreement between the two. This novel method provides an efficient way to correlate regime transition with other data sets, with additional insights into the mechanical response of the contact compared to other regime transition criteria. Possible applications of this method include enabling smart asset monitoring and in the development of engineering components that are subject to fretting. This is an extremely flexible technique that has applicability for other types of loop analysis.

Published
2020

9. Real-time fretting loop regime transition identification using acoustic emissions

Author

Wade, A, Copley, R, Clarke, B, Alsheikh Omar, A, Beadling, AR, Liskiewicz, T, Bryant, MG, Wade, A, Copley, R, Clarke, B, Alsheikh Omar, A, Beadling, AR, Liskiewicz, T, and Bryant, MG

Abstract

© 2020 Elsevier Ltd Acoustic emission (AE) has been successfully used to investigate the damage mechanisms of fretting contacts within different regimes. This study investigated the transition between fretting regimes using the relationship between AE and the mechanical response of a dry, steel-on-steel, ball-on-flat contact under different tangential displacements achieving the partial slip regime, mixed fretting regime and gross slip regime. Increased AE response occurred during gross-slip events and there was strong positive correlation between AE and fretting energy ratio. The relationship was strongest when gross sliding was experienced allowing identification of transition from the partial slip to the gross slip regime. This makes AE a good candidate to detect regime transition in-situ due to ease of integration and its non-destructive nature.

Published
2020

11. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

12. Pelagia noctiluca as a model to uncover scyphozoan developmental mechanisms

Author

Kraus, Y., Copley, R., Aury, J.M., Rentzsch, F., Lombard, F., Guidi, L, Leclere, L., Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department for Molecular Evolution and Development, University of Vienna [Vienna], Laboratoire d'océanographie de Villefranche (LOV), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV)

Subjects
[SDU.STU.OC]Sciences of the Universe [physics]/Earth Sciences/Oceanography
Abstract

International audience

Published
2019

13. Real-time fretting loop regime transition identification using acoustic emissions

Author

Wade, A, Copley, R, Clarke, B, Alsheikh Omar, A, Beadling, AR, Liskiewicz, T, Bryant, MG, Wade, A, Copley, R, Clarke, B, Alsheikh Omar, A, Beadling, AR, Liskiewicz, T, and Bryant, MG

Abstract

© 2020 Elsevier Ltd Acoustic emission (AE) has been successfully used to investigate the damage mechanisms of fretting contacts within different regimes. This study investigated the transition between fretting regimes using the relationship between AE and the mechanical response of a dry, steel-on-steel, ball-on-flat contact under different tangential displacements achieving the partial slip regime, mixed fretting regime and gross slip regime. Increased AE response occurred during gross-slip events and there was strong positive correlation between AE and fretting energy ratio. The relationship was strongest when gross sliding was experienced allowing identification of transition from the partial slip to the gross slip regime. This makes AE a good candidate to detect regime transition in-situ due to ease of integration and its non-destructive nature.

Published
2019

14. MicroRNAs that contribute to coordinating the immune response in Drosophila melanogaster

Author

Atilano, M, Glittenberg, M, Monteiro, A, Copley, R, and Ligoxygakis, P

Abstract

Small noncoding RNAs called microRNAs (miRNAs) have emerged as post-transcriptional regulators of gene expression related to host defenses. Here, we have used Drosophila melanogaster to explore the contribution of individual or clusters of miRNAs in countering systemic Candida albicans infection. From a total of 72 tested, we identify 6 miRNA allelic mutant backgrounds that modulate the survival response to infection and the ability to control pathogen number. These mutants also exhibit dysregulation of the Toll pathway target transcripts Drosomycin (Drs) and Immune-Induced Molecule 1 (IM1). These are characteristics of defects in Toll signaling, and consistent with this, we demonstrate dependency for one of the miRNA mutants on the NF-κΒ homolog Dif. We also quantify changes in the miRNA expression profile over time in response to three pathogen types, and identify 13 mature miRNA forms affected by pathogens that stimulate Toll signaling. To complement this, we provide a genome-wide map of potential NF-κB sites in proximity to miRNA genes. Finally, we demonstrate that systemic C. albicans infection contributes to a reduction in the total amount of branch-chained amino acids, which is miRNA-regulated. Overall, our data reveal a new layer of miRNA complexity regulating the fly response to systemic fungal infection.

Published
2017

16. A structural analysis of phosphate and sulphate binding sites in proteins. Estimation of propensities for binding and conservation of phosphate binding sites

Author

Copley, R. R. and Geoffrey John Barton

Subjects
Structural Biology, Molecular Biology
Abstract

The high resolution X-ray structures of 38 proteins that bind phosphate containing groups and 36 proteins binding sulphate ions were analysed to characterise the structural features of anion binding sites in proteins. 34 of the 66 phosphates found were in close proximity to the amino terminus of an alpha-helix. 27% of phosphate groups bind to only one amino acid, but there is a wide distribution, with 3% of phosphates binding to seven residues. Similarly, there is a large variability in the number of contacts each phosphate group makes to the protein. This ranges from none (3% of phosphates) to nine (3% of phosphates). The most common number of contacts is two (23% of phosphates). The most commonly found residue at helix-type binding sites is glycine, followed by Arg, Thr, Ser and Lys. At non-helix binding sites, the most commonly found residue is Arg followed by Tyr, His, Lys and Ser. There is no typical phosphate binding site. There are marked differences between propensities for phosphate binding at helix and non-helix type binding sites. Non-helix binding sites show more discrimination between the types of residues involved in binding when compared to the helix set. The propensities for binding of the amino acids reveal the expected trend of positively charged and polar residues being good at binding (although that for lysine is unexpectedly low) with the bulky non-polar residues being poor at binding. Bulky residues are less likely to bind with the amide nitrogen. Sulphate binding sites show similar trends. Analysis of multiple sequence alignments that include phosphate and sulphate binding proteins reveals the degree of conservation at the binding site residues compared to the average conservation of residues in the protein. Phosphate binding site residues are more conserved than sulphate binding sites.

Published
2016

19. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

Author

Martin, H, Kim, G, Pagnamenta, A, Murakami, Y, Carvill, G, Meyer, E, Copley, R, Rimmer, A, Barcia, G, Fleming, MR, Kronengold, J, Brown, MR, Hudspith, K, Broxholme, J, Kanapin, A, Cazier, J, Kinoshita, T, Nabbout, R, Bentley, D, McVean, G, Heavin, S, Zaiwalla, Z, McShane, T, Mefford, H, Shears, D, Stewart, H, Kurian, M, Scheffer, I, Blair, E, Donnelly, P, Kaczmarek, L, and Taylor, J

Subjects
Male, Epilepsy, NAV1.2 Voltage-Gated Sodium Channel, Potassium Channels, High-Throughput Nucleotide Sequencing, Membrane Proteins, Nerve Tissue Proteins, Articles, Potassium Channels, Sodium-Activated, Uniparental Disomy, Young Adult, Child, Preschool, Mutation, Humans, KCNQ2 Potassium Channel, Genetic Predisposition to Disease, Proto-Oncogene Proteins c-cbl, Pathology, Molecular, Child, Chromosomes, Human, Pair 9, Genome-Wide Association Study
Abstract

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

Published
2014

23. New developments in the InterPro database

Author

Mulder, N. J., primary, Apweiler, R., additional, Attwood, T. K., additional, Bairoch, A., additional, Bateman, A., additional, Binns, D., additional, Bork, P., additional, Buillard, V., additional, Cerutti, L., additional, Copley, R., additional, Courcelle, E., additional, Das, U., additional, Daugherty, L., additional, Dibley, M., additional, Finn, R., additional, Fleischmann, W., additional, Gough, J., additional, Haft, D., additional, Hulo, N., additional, Hunter, S., additional, Kahn, D., additional, Kanapin, A., additional, Kejariwal, A., additional, Labarga, A., additional, Langendijk-Genevaux, P. S., additional, Lonsdale, D., additional, Lopez, R., additional, Letunic, I., additional, Madera, M., additional, Maslen, J., additional, McAnulla, C., additional, McDowall, J., additional, Mistry, J., additional, Mitchell, A., additional, Nikolskaya, A. N., additional, Orchard, S., additional, Orengo, C., additional, Petryszak, R., additional, Selengut, J. D., additional, Sigrist, C. J. A., additional, Thomas, P. D., additional, Valentin, F., additional, Wilson, D., additional, Wu, C. H., additional, and Yeats, C., additional

Published
2007
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31. Novel protein domains and repeats in Drosophila melanogaster: insights into structure, function, and evolution.

Author

Ponting, C P, Mott, R, Bork, P, and Copley, R R

Abstract

Sequence database searching methods such as BLAST, are invaluable for predicting molecular function on the basis of sequence similarities among single regions of proteins. Searches of whole databases however, are not optimized to detect multiple homologous regions within a single polypeptide. Here we have used the prospero algorithm to perform self-comparisons of all predicted Drosophila melanogaster gene products. Predicted repeats, and their homologs from all species, were analyzed further to detect hitherto unappreciated evolutionary relationships. Results included the identification of novel tandem repeats in the human X-linked retinitis pigmentosa type-2 gene product, repeated segments in cystinosin, associated with a defect in cystine transport, and 'nested' homologous domains in dysferlin, whose gene is mutated in limb girdle muscular dystrophy. Novel signaling domain families were found that may regulate the microtubule-based cytoskeleton and ubiquitin-mediated proteolysis, respectively. Two families of glycosyl hydrolases were shown to contain internal repetitions that hint at their evolution via a piecemeal, modular approach. In addition, three examples of fruit fly genes were detected with tandem exons that appear to have arisen via internal duplication. These findings demonstrate how completely sequenced genomes can be exploited to further understand the relationships between molecular structure, function, and evolution.

Published
2001
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32. SMART: a web-based tool for the study of genetically mobile domains.

Author

Schultz, J, Copley, R R, Doerks, T, Ponting, C P, and Bork, P

Abstract

SMART (a Simple Modular Architecture Research Tool) allows the identification and annotation of genetically mobile domains and the analysis of domain architectures (http://SMART.embl-heidelberg.de ). More than 400 domain families found in signalling, extra-cellular and chromatin-associated proteins are detectable. These domains are extensively annotated with respect to phyletic distributions, functional class, tertiary structures and functionally important residues. Each domain found in a non-redundant protein database as well as search parameters and taxonomic information are stored in a relational database system. User interfaces to this database allow searches for proteins containing specific combinations of domains in defined taxa.

Published
2000
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34. New Halogenated Sesquiterpenes from South African Specimens of the Circumtropical Sea Hare Aplysia dactylomela

Author

McPhail, K. L., Davies-Coleman, M. T., Copley, R. C. B., and Eggleston, D. S.

Abstract

An examination of the digestive gland extracts from two color variants of the circumtropical sea hare Aplysia dactylomela, collected off the Eastern Cape coast of South Africa, yielded four new halogenated sesquiterpenes:  algoane (1), 1-deacetoxyalgoane (2), 1-deacetoxy-8-deoxyalgoane (3), and ibhayinol (4). The known sesquiterpenes, nidificene (5) and prepacifenol epoxide (6), were also isolated from the A. dactylomela extracts. Standard spectroscopic techniques were used to determine the structures of compounds 1−6, with a single-crystal X-ray diffraction experiment establishing the structure of 1 and providing the absolute stereochemistry of this compound.

Published
1999

35. What You Can Offer When a Newborn Infant Dies

Author

Copley R and Blackburn C

Subjects
Advanced and Specialized Nursing, Pediatrics, medicine.medical_specialty, business.industry, Assessment and Diagnosis, Emergency Nursing, LPN and LVN, Critical Care Nursing, medicine.disease, Infant newborn, Moment (mathematics), medicine, Medical emergency, business
Published
1989
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36. The Fdddfour‐circle diffractometer for single‐crystal X‐ray studies at temperatures down to 9 K

Author

Copley, R. C. B., Goeta, A. E., Lehmann, C. W., Cole, J. C., Yufit, D. S., Howard, J. A. K., and Archer, J. M.

Abstract

The Fdddfour‐circle diffractometer system has been developed to perform X‐ray diffraction experiments at temperatures as low as 9 K. The diffractometer consists of: (i) a Siemens rotating‐anode generator; (ii) a Huber goniometer with offset X circle; (iii) a Siemens Fast Scintillation Detector; and (iv) an APD `202' Displex cryogenic refrigerator. The belt‐driven rotating anode gives an X‐ray flux that is far in excess of that obtained from a sealed X‐ray tube and leads to faster data collections and the opportunity to study smaller samples. X‐ray beam alignment requires precise movements of the 300 kg goniometer and this is achieved using compressed air pads. Steel‐braided gas lines that allow the transfer of helium gas between the Displex and the compressor are supported by a counterbalance system. The stress on these lines has been reduced by attaching them to the Displex viahigh‐pressure rotating joints and by passing them through a metal ring that is attached to the χcircle. A compact vacuum gauge has been mounted through one of the four ports on the top of the cryostat and gives valuable information on the pressure within the Displex sample chamber during an experiment. Crystals are mounted on sharpened 0.3 mm graphite pencil leads that are held in a newly designed sample mount. The temperature reported from the second stage of the Displex has been assessed by consideration of temperature standards that include the solid‐state phase transitions of benzil (1,2‐diphenylethanedione) and terbium vanadate.

Published
1997
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40. Absolute Stereochemistry of Ibhayinol from a South African Sea Hare

Author

Copley, R. C. B., Davies-Coleman, M. T., Edmonds, D. R., Faulkner, D. J., and McPhail, K. L.

Abstract

The absolute stereochemistry of the tricyclic, sesquiterpene ibhayinol (5) extracted from the sea hare Aplysia dactylomela, collected in Algoa Bay, South Africa, was established as 1S, 3S, 4S, 6R, 7S, 10R, 11S from a single-crystal X-ray diffraction experiment. The structure of ibhayinol suggested that 8-dehydroxy-1-deacetylalgoane (7) might be a biosynthetic precursor of this compound.

Published
2002
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41. Synthesis of Chiral 1,2-Diamines by Asymmetric Lithiation−Substitution

Author

Coldham, I., Copley, R. C. B., Haxell, T. F. N., and Howard, S.

Abstract

The imidazolidine (tetrahydroimidazole) 2, prepared in one step from N-iso-propylethylenediamine, was subjected to asymmetric lithiation and substitution using sec-butyllithium, (−)-sparteine and a range of electrophiles. Substituted imidazolidines were formed with high optical purity and could be hydrolyzed under acidic conditions to chiral, substituted ethylenediamines. Kinetic data indicate that the conformation of the carbonyl group is crucial to the extent of deprotonation, and this has implications for the lithiation of unsymmetrical carbamates and carboxylic amides.

Published
2001

45. The EH1 motif in metazoan transcription factors

Author

Copley Richard R

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The Engrailed Homology 1 (EH1) motif is a small region, believed to have evolved convergently in homeobox and forkhead containing proteins, that interacts with the Drosophila protein groucho (C. elegans unc-37, Human Transducin-like Enhancers of Split). The small size of the motif makes its reliable identification by computational means difficult. I have systematically searched the predicted proteomes of Drosophila, C. elegans and human for further instances of the motif. Results Using motif identification methods and database searching techniques, I delimit which homeobox and forkhead domain containing proteins also have likely EH1 motifs. I show that despite low database search scores, there is a significant association of the motif with transcription factor function. I further show that likely EH1 motifs are found in combination with T-Box, Zinc Finger and Doublesex domains as well as discussing other plausible candidate associations. I identify strong candidate EH1 motifs in basal metazoan phyla. Conclusion Candidate EH1 motifs exist in combination with a variety of transcription factor domains, suggesting that these proteins have repressor functions. The distribution of the EH1 motif is suggestive of convergent evolution, although in many cases, the motif has been conserved throughout bilaterian orthologs. Groucho mediated repression was established prior to the evolution of bilateria.

Published
2005
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46. Variation in structural location and amino acid conservation of functional sites in protein domain families

Author

Copley Richard R, Pils Birgit, and Schultz Jörg

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The functional sites of a protein present important information for determining its cellular function and are fundamental in drug design. Accordingly, accurate methods for the prediction of functional sites are of immense value. Most available methods are based on a set of homologous sequences and structural or evolutionary information, and assume that functional sites are more conserved than the average. In the analysis presented here, we have investigated the conservation of location and type of amino acids at functional sites, and compared the behaviour of functional sites between different protein domains. Results Functional sites were extracted from experimentally determined structural complexes from the Protein Data Bank harbouring a conserved protein domain from the SMART database. In general, functional (i.e. interacting) sites whose location is more highly conserved are also more conserved in their type of amino acid. However, even highly conserved functional sites can present a wide spectrum of amino acids. The degree of conservation strongly depends on the function of the protein domain and ranges from highly conserved in location and amino acid to very variable. Differentiation by binding partner shows that ion binding sites tend to be more conserved than functional sites binding peptides or nucleotides. Conclusion The results gained by this analysis will help improve the accuracy of functional site prediction and facilitate the characterization of unknown protein sequences.

Published
2005
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