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Francis A Barr - One of the best experts on this subject based on the ideXlab platform.

  • a pp2a b55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit
    Journal of Cell Biology, 2016
    Co-Authors: Michael J Cundell, Lukas Hutter, Ricardo Nunes Bastos, Elena Poser, James Holder, Shabaz Mohammed, Bela Novak, Francis A Barr
    Abstract:

    PP2A-B55 is one of the major phosphatases regulating cell division. Despite its importance for temporal control during mitotic exit, how B55 substrates are recognized and differentially dephosphorylated is unclear. Using phosphoproteomics combined with kinetic modeling to extract B55-dependent rate constants, we have systematically identified B55 substrates and assigned their temporal order in mitotic exit. These substrates share a bipartite polybasic recognition determinant (BPR) flanking a Cdk1 phosphorylation site. Experiments and modeling show that dephosphorylation rate is encoded into B55 substrates, including its inhibitor ENSA, by cooperative action of basic residues within the BPR. A complementary acidic surface on B55 decodes this signal, supporting a cooperative electrostatic mechanism for substrate selection. A further level of specificity is encoded into B55 substrates because B55 displays selectivity for phosphothreonine. These simple biochemical properties, combined with feedback control of B55 activity by the phosphoserine-containing substrate/inhibitor ENSA, can help explain the temporal sequence of events during exit from mitosis.

Alexander S Mankin - One of the best experts on this subject based on the ideXlab platform.

  • how macrolide antibiotics work
    Trends in Biochemical Sciences, 2018
    Co-Authors: Nora Vazquezlaslop, Alexander S Mankin
    Abstract:

    Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus, macrolides have been viewed as ‘tunnel plugs’ that stop the synthesis of every protein. More recent evidence, however, demonstrates that macrolides selectively inhibit the translation of a subset of cellular proteins, and that their action crucially depends on the nascent protein sequence and on the antibiotic structure. Therefore, macrolides emerge as modulators of translation rather than as global inhibitors of protein synthesis. The context-specific action of macrolides is the basis for regulating the expression of resistance genes. Understanding the details of the mechanism of macrolide action may inform rational design of new drugs and unveil important principles of translation regulation.

  • structures of proline rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition
    Nucleic Acids Research, 2016
    Co-Authors: Matthieu G Gagnon, Tanja Florin, Alexander S Mankin, Raktim N Roy, Ivan B Lomakin, Thomas A Steitz
    Abstract:

    With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71 -35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71 -35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.

  • the general mode of translation inhibition by macrolide antibiotics
    Proceedings of the National Academy of Sciences of the United States of America, 2014
    Co-Authors: Krishna Kannan, Pinal Kanabar, David Schryer, Tanja Florin, Neil Bahroos, Tanel Tenson, Eugene Oh, Jonathan S Weissman, Alexander S Mankin
    Abstract:

    Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. To understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5′-proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The problematic sequence motifs are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segment that contacts the antibiotic molecule in the exit tunnel. Therefore, it appears that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not functioning during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics.

  • macrolide antibiotics in the ribosome exit tunnel species specific binding and action
    Annals of the New York Academy of Sciences, 2011
    Co-Authors: Krishna Kannan, Alexander S Mankin
    Abstract:

    : Macrolide antibiotics bind in the nascent peptide exit tunnel of the ribosome and inhibit protein synthesis. The majority of information on the principles of binding and action of these antibiotics comes from studies that employed model organisms. However, there is a growing understanding that the binding of macrolides to their target, as well as the mode of inhibition of translation, can be strongly influenced by variations in ribosome structure between bacterial species. Awareness of the existence of species-specific differences in drug action and appreciation of the extent of these differences can stimulate future work on developing better macrolide drugs. In this review, representative cases illustrating the organism-specific binding and action of macrolide antibiotics, as well as species-specific mechanisms of resistance are analyzed.

Kenneth B Kaplan - One of the best experts on this subject based on the ideXlab platform.

  • chromosome passenger complexes control anaphase duration and spindle elongation via a kinesin 5 brake
    Journal of Cell Biology, 2011
    Co-Authors: Daniel K Rozelle, Scott D Hansen, Kenneth B Kaplan
    Abstract:

    During mitosis, chromosome passenger complexes (CPCs) exhibit a well-conserved association with the anaphase spindle and have been implicated in spindle stability. However, their precise effect on the spindle is not clear. In this paper, we show, in budding yeast, that a CPC consisting of CBF3, Bir1, and Sli15, but not Ipl1, is required for normal spindle elongation. CPC mutants slow spindle elongation through the action of the bipolar kinesins Cin8 and Kip1. The same CPC mutants that slow spindle elongation also result in the enrichment of Cin8 and Kip1 at the spindle midzone. Together, these findings argue that CPCs function to organize the spindle midzone and potentially switch motors between force generators and molecular brakes. We also find that slowing spindle elongation delays the mitotic exit network (MEN)-dependent release of Cdc14, thus delaying spindle breakdown until a minimal spindle size is reached. We propose that these CPC- and MEN-dependent mechanisms are important for coordinating chromosome segregation with spindle breakdown and mitotic exit.

  • chromosome passenger complexes control anaphase duration and spindle elongation via a kinesin 5 brake
    Journal of Cell Biology, 2011
    Co-Authors: Daniel K Rozelle, Scott D Hansen, Kenneth B Kaplan
    Abstract:

    During mitosis, chromosome passenger complexes (CPCs) exhibit a well-conserved association with the anaphase spindle and have been implicated in spindle stability. However, their precise effect on the spindle is not clear. In this paper, we show, in budding yeast, that a CPC consisting of CBF3, Bir1, and Sli15, but not Ipl1, is required for normal spindle elongation. CPC mutants slow spindle elongation through the action of the bipolar kinesins Cin8 and Kip1. The same CPC mutants that slow spindle elongation also result in the enrichment of Cin8 and Kip1 at the spindle midzone. Together, these findings argue that CPCs function to organize the spindle midzone and potentially switch motors between force generators and molecular brakes. We also find that slowing spindle elongation delays the mitotic exit network (MEN)–dependent release of Cdc14, thus delaying spindle breakdown until a minimal spindle size is reached. We propose that these CPC- and MEN-dependent mechanisms are important for coordinating chromosome segregation with spindle breakdown and mitotic exit.

Michael J Cundell - One of the best experts on this subject based on the ideXlab platform.

  • a pp2a b55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit
    Journal of Cell Biology, 2016
    Co-Authors: Michael J Cundell, Lukas Hutter, Ricardo Nunes Bastos, Elena Poser, James Holder, Shabaz Mohammed, Bela Novak, Francis A Barr
    Abstract:

    PP2A-B55 is one of the major phosphatases regulating cell division. Despite its importance for temporal control during mitotic exit, how B55 substrates are recognized and differentially dephosphorylated is unclear. Using phosphoproteomics combined with kinetic modeling to extract B55-dependent rate constants, we have systematically identified B55 substrates and assigned their temporal order in mitotic exit. These substrates share a bipartite polybasic recognition determinant (BPR) flanking a Cdk1 phosphorylation site. Experiments and modeling show that dephosphorylation rate is encoded into B55 substrates, including its inhibitor ENSA, by cooperative action of basic residues within the BPR. A complementary acidic surface on B55 decodes this signal, supporting a cooperative electrostatic mechanism for substrate selection. A further level of specificity is encoded into B55 substrates because B55 displays selectivity for phosphothreonine. These simple biochemical properties, combined with feedback control of B55 activity by the phosphoserine-containing substrate/inhibitor ENSA, can help explain the temporal sequence of events during exit from mitosis.

Jonathan S Davies - One of the best experts on this subject based on the ideXlab platform.

  • the limits of partnership an exit action strategy for local democratic inclusion
    Social Science Research Network, 2011
    Co-Authors: Jonathan S Davies
    Abstract:

    The challenge of enhancing the ‘democratic anchorage’ of partnerships has become a central concern in policy studies. Radical reform proposals designed to level the deliberative playing field include community veto powers and the appointment of neutral arbiters. Welcome as they would be, however, it is questionable whether such reforms would overcome power asymmetries in the partnership arena. A study of the local politics of social inclusion in two UK cities, Dundee and Hull, suggests that managerialism, driven by national governments, is eroding the prospects for partnership democratisation. But more significantly for the reformist agenda, public managers and community activists think in incompatible frames about the role of partnerships and in ways that are not understood by the other party. Non-communication undermines the prospects for an equitable deliberative consensus. Insights from Bourdieu suggest that even in more favourable deliberative environments than those in Dundee and Hull, subtle manifestations of power in culture, discourse and bearing would undermine the potential for a Habermasian consensus between radically unequal actors. In a radical departure from the network governance paradigm, it is therefore argued that empowerment may depend less on enhanced network democracy than on strong independent community organisation capable of acting separately and coercively against governing institutions and elites – an Exit-Action strategy. These preliminary conclusions point to a substantial research agenda on the politics of the state-civil society nexus.

  • the limits of partnership an exit action strategy for local democratic inclusion
    Political Studies, 2007
    Co-Authors: Jonathan S Davies
    Abstract:

    The challenge of enhancing the `democratic anchorage' of partnerships has become a central concern in policy studies. Radical reform proposals designed to level the deliberative playing field include community veto powers and the appointment of neutral arbiters. Welcome as they would be, however, it is questionable whether such reforms would overcome power asymmetries in the partnership arena. A study of the local politics of social inclusion in two UK cities, Dundee and Hull, suggests that managerialism, driven by national governments, is eroding the prospects for partnership democratisation. But more significantly for the reformist agenda, public managers and community activists think in incompatible frames about the role of partnerships and in ways that are not understood by the other party. Non-communication undermines the prospects for an equitable democratic consensus. Insights from Bourdieu suggest that even in environments more favourable to equitable democratic discourse than those in Dundee and Hull, subtle manifestations of power in culture, discourse and bearing would undermine the potential for a Habermasian consensus between radically unequal actors. In a radical departure from the network governance paradigm, it is therefore argued that empowerment may depend less on enhanced network democracy than on strong independent community organisation capable of acting separately and coercively against governing institutions and elites - an Exit-Action strategy. These preliminary conclusions point to a substantial research agenda on the politics of the state-civil society nexus.