Volume 10 Issue 12, December 2014

In the assembly of metalloenzymes, the matching of metals and proteins must occur with absolute precision. When zinc-starved, Chlamydomonas maintains its balance of metals by sequestering copper in electron-dense traps for metals, thus preventing mishaps in protein metallation.

The dynamic interplay between p53 and Mdm2 triggers cell cycle arrest after DNA damage. A new study reveals that disorder in the transactivation domain of p53 is important for tuning this negative feedback system to ensure normal cellular signaling responses.

The small molecule inflachromene was discovered as a microglia-selective inhibitor of the central nervous system proinflammatory response and found to target HMGB2 and HMGB1 to impair proinflammatory signaling in microglia, resulting in neuroprotection.

Carbohydrate antigens on HIV are important for viral biology as well as for recognition by glycan-reactive broadly neutralizing antibodies such as 2G12. A review of recent strategies targeting HIV glycans discusses the characterization and manipulation of glycopeptide epitopes for use as potential vaccines.

Increasing residual helicity in the p53 transcriptional activation domain strengthened interactions with Mdm2, resulting in alterations in p53 protein dynamics, impaired transcription of target genes and failure to promote cell cycle arrest.

Diels-Alder chemistry is widely used for bioconjugations, and one variant of the reaction can ‘deprotect’ a small molecule via spontaneous elimination. This activation chemistry is now demonstrated on biomolecules in cells at high yields in 10 minutes.

The use of ATP competitive kinase inhibitors against the pseudokinase Her3 has been largely unsuccessful. Hydrophobic tagging of a covalent kinase inhibitor promotes Her3 degradation and prevents productive dimerization and signaling.

A small-molecule inhibitor of the type III phosphatidylinositol 3-kinase, Vps34, binds the ATP binding pocket and prevents vesicle trafficking and autophagy.

A new synthetic biology circuit using recombinases to control the timing of downstream steps allows 1,000-fold differences in signal between on and off states, facilitating cell identification and selective turn-on of cytotoxic agents.

Biosynthesis of the strigolactones—important plant hormones—has been solved up to carlactone. Biochemical and genetic evidence now demonstrate that homologous enzymes perform two subsequent oxidations, setting the strigolactone scaffold in place.

A collection of chemical tools and spectroscopic techniques demonstrate that Zn availability influences Cu⁺ storage and localization in the green alga Chlamydomonas, with Zn limitation causing the accumulation of Cu⁺ in lysosome-related organelles.

By biochemical purification and functional validation using knockout animals, ENPP1 is now defined as a major hydrolase for 2′,3′-cGAMP, a cyclic dinucleotide generated during antiviral innate immunity. New nonhydrolyzable 2′,3′-cGAMP analogs are potent activators of this system.

Activity-based probes (ABPs) are widely used for system-wide profiling of enzymatic activity. Electrophilic ABPs applied to genomic RNA libraries led to the isolation of a 42-nt RNA motif that was adapted as an alkylation-based RNA labeling strategy.

A screen for inhibitors of microglial activation of neuroinflammation identified the compound ICM, which is anti-inflammatory and neuroprotective by targeting HMGB1 and HMGB2, implicating these proteins in a toxic microglial response.

β₂-adrenergic receptor–mediated cAMP signaling from internal compartments is more effective compared to the plasma membrane in regulating a distinct set of genes, demonstrating a functional significance for the spatial separation of cAMP signaling.

A modification of the in silico screening tool, DOCK, allows for identification of compounds that covalently modify catalytic and noncatalytic protein nucleophiles to modulate the activities of bacterial β-lactamase and the kinases RSK2, MSK1 and JAK3.