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Withdrawal from multilateral treaties
\"This is the first comprehensive and systematic monograph on withdrawal from multilateral treaties, which explains the evolution of the concept of withdrawal and examines its increasing in the context of the international law of treaties. It examines the political and legal framework around treaty making to explain the evolution of withdrawal over time and its increasing use overtime. International scholars and policy makers have long addressed treaty making and treaty maintenance in light of the binary choice between compliance and breach, while leaving unregulated or at least under-regulated the actula act of withdrawal. In the age of global entrenchment, is there still room for international law to regulate the rules of the game, or will unilateral decisions overturn the current architecture of a multilateral gloabl order?\"-- Provided by publisher.
BOOK
The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center
Translation termination is an essential cellular process, which is also of therapeutic interest for diseases that manifest from premature stop codons. In eukaryotes, translation termination requires eRF1, which recognizes stop codons, catalyzes the release of nascent proteins from ribosomes and facilitates ribosome recycling. The small molecule SRI-41315 triggers eRF1 degradation and enhances translational readthrough of premature stop codons. However, the mechanism of action of SRI-41315 on eRF1 and translation is not known. Here we report cryo-EM structures showing that SRI-41315 acts as a metal-dependent molecular glue between the N domain of eRF1 responsible for stop codon recognition and the ribosomal subunit interface near the decoding center. Retention of eRF1 on ribosomes by SRI-41315 leads to ribosome collisions, eRF1 ubiquitylation and a higher frequency of translation termination at near-cognate stop codons. Our findings reveal a new mechanism of release factor inhibition and additional implications for pharmacologically targeting eRF1.
The small molecule SRI-41315 induces the degradation of the translation termination factor eRF1 to enhance stop codon readthrough. Coelho, Yip et al. reveal that SRI-41315 is a metal-dependent molecular glue that traps eRF1 on terminating ribosomes.
Journal Article
Negotiating with the devil : inside the world of armed conflict mediation
After many years in the little-known world of back-channel mediation, helping sworn adversaries to prevent, manage or resolve conflict, Pierre Hazan felt compelled to re-examine the acute practical and ethical dilemmas that affected his work in Bosnia, Ukraine, the Sahel and the Central African Republic. What is the mediator's responsibility when two belligerents conclude a peace agreement to the detriment of a third? Should mediators never be party to 'ethnic cleansing', even if it saves lives? Is a fragile peace worth sacrificing justice for-or will that sacrifice fuel another cycle of violence? In an increasingly dystopian world, this book offers both practical guidelines and a moral compass for mediators whose field of action has transformed dramatically.
Book
A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion
Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.
Premature termination codons can cause early translation termination and lead to disease. Here the authors perform a screen to identify compounds with readthrough activity and show that these reduce eRF1 levels to suppress premature termination associated with cystic fibrosis.
Journal Article
The ribosome termination complex remodels release factor RF3 and ejects GDP
Translation termination involves release factors RF1, RF2 and the GTPase RF3 that recycles RF1 and RF2 from the ribosome. RF3 dissociates from the ribosome in the GDP-bound form and must then exchange GDP for GTP. The 70S ribosome termination complex (70S-TC) accelerates GDP exchange in RF3, suggesting that the 70S-TC can function as the guanine nucleotide exchange factor for RF3. Here, we use cryogenic-electron microscopy to elucidate the mechanism of GDP dissociation from RF3 catalyzed by the
Escherichia coli
70S-TC. The non-rotated ribosome bound to RF1 remodels RF3 and induces a peptide flip in the phosphate-binding loop, efficiently ejecting GDP. Binding of GTP allows RF3 to dock at the GTPase center, promoting the dissociation of RF1 from the ribosome. The structures recapitulate the functional cycle of RF3 on the ribosome and uncover the mechanism by which the 70S-TC allosterically dismantles the phosphate-binding groove in RF3, a previously overlooked function of the ribosome.
Li et al. reveal the mechanism by which the ribosome termination complex catalyzes dissociation of GDP from release factor RF3 in
Escherichia coli
. The findings explain the guanine nucleotide exchange factor activity of the ribosome.
Journal Article
Phase separation of a yeast prion protein promotes cellular fitness
Much recent work has focused on liquid-liquid phase separation as a cellular response to changing physicochemical conditions. Because phase separation responds critically to small changes in conditions such as pH, temperature, or salt, it is in principle an ideal way for a cell to measure and respond to changes in the environment. Small pH changes could, for instance, induce phase separation of compartments that store, protect, or inactivate proteins. Franzmann
et al.
used the yeast translation termination factor Sup35 as a model for a phase separation–induced stress response. Lowering the pH induced liquid-liquid phase separation of Sup35. The resulting liquid compartments subsequently hardened into gels, which sequestered the termination factor. Raising the pH triggered dissolution of the gels, concomitant with translation restart. Protecting Sup35 in gels could provide a fitness advantage to recovering yeast cells that must restart the translation machinery after stress.
Science
, this issue p.
eaao5654
The prion domain of Sup35 is a pH sensor that promotes stress survival by phase separation.
Despite the important role of prion domains in neurodegenerative disease, their physiological function has remained enigmatic. Previous work with yeast prions has defined prion domains as sequences that form self-propagating aggregates. Here, we uncovered an unexpected function of the canonical yeast prion protein Sup35. In stressed conditions, Sup35 formed protective gels via pH-regulated liquid-like phase separation followed by gelation. Phase separation was mediated by the N-terminal prion domain and regulated by the adjacent pH sensor domain. Phase separation promoted yeast cell survival by rescuing the essential Sup35 translation factor from stress-induced damage. Thus, prion-like domains represent conserved environmental stress sensors that facilitate rapid adaptation in unstable environments by modifying protein phase behavior.
Journal Article
An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome
Antimicrobial peptide Api137 inhibits translation by trapping release factors 1 or 2 associated with ribosomes and arresting termination.
Many antibiotics stop bacterial growth by inhibiting different steps of protein synthesis. However, no specific inhibitors of translation termination are known. Proline-rich antimicrobial peptides, a component of the antibacterial defense system of multicellular organisms, interfere with bacterial growth by inhibiting translation. Here we show that Api137, a derivative of the insect-produced antimicrobial peptide apidaecin, arrests terminating ribosomes using a unique mechanism of action. Api137 binds to the
Escherichia coli
ribosome and traps release factor (RF) RF1 or RF2 subsequent to the release of the nascent polypeptide chain. A high-resolution cryo-EM structure of the ribosome complexed with RF1 and Api137 reveals the molecular interactions that lead to RF trapping. Api137-mediated depletion of the cellular pool of free release factors causes the majority of ribosomes to stall at stop codons before polypeptide release, thereby resulting in a global shutdown of translation termination.
Journal Article