Articles in 2011

Understanding how complexes, such as Mediator, that act at diverse promoters interact with gene-specific transcription factors is key to understanding transcriptional regulation. The solution structure of Med25 (Arc92) is now presented and its interaction with helices on the VP16 activator elucidated. The Med25 interface is found to be conserved, but VP16 is revealed to be more diverse in its interaction with different interactors.

Herpesvirus VP16 is a classic example of a transcriptional activator and interacts with the Mediator complex via MED25 (ARC92). The structure of the VP16 interaction domain from MED25 is now solved and the binding site for the VP16 transactivation domain defined, giving insight into how a transcription activator contacts a key component involved in transcription initiation.

Allosteric effectors have the ability to modulate protein-ligand interactions in a controlled fashion. Now a novel class of antibody-like affinity reagents, synthetic antigen binders or sABs, are generated in vitro that target either the open or closed form of maltose-binding protein. These sABs can be engineered to control ligand-binding affinities by modulating the transition between different conformations.

In this issue, a wide array of structural and biochemical techniques are applied to reveal the molecular details of activity regulation in one of life's most essential enzymes, the ribonucleotide reductase.

Glutamate receptor ion channels use the free energy of ligand binding to trigger ion channel activation and desensitization. In this issue, an analysis of all-atom molecular dynamics simulations dissects the binding process, reveals a substantial gain in free energy produced by domain closure for agonists and reports unique energy landscapes for individual ligands.

RNA Pol III transcribes a number of non-coding RNA types. The crystal structure of hRPC62, part of a ternary subcomplex of RNA Pol III needed for specific initiation, is now described along with its interactions within the subcomplex. hRPC62 shares structural features with the general Pol II transcription factor TFIIEα, indicating functional similarities between components needed for promoter-specific initiation in the two systems.

Alternative splicing is a regulated process that increases the coding potential of the genome by including or excluding exons. The covalent histone modification H3K9me3, as well as HP1γ,which binds this modification, are now shown to participate in a mechanism that tags a subset of variant exons for inclusion.

Discrimination between self and non-self surfaces by the complement system of innate immunity has long been enigmatic. Finally, two papers provide structural insights into host protection against indiscriminate immune surveillance.

The signal sequence on nascent peptides is recognized by the signal recognition particle (SRP), with subsequent targeting of the SRP-ribosomal nascent complex to the membrane. The structure of a signal sequence bound to the core SRP is presented, revealing structural changes in the SRP upon signal sequence binding.

Insulin secretion from pancreatic b cells is tightly regulated. Using chromosome conformation capture techniques, it is now found that the insulin promoter locus forms a long-range glucose-regulated interaction with SYT8, linked here to insulin secretion. SYT8 expression is affected concordantly with changes in insulin expression, suggesting a mechanism whereby insulin expression and secretion might be coordinated.

Ribonucleotide reductase is essential to maintain the cellular pools of dNTPs, and its activity is controlled allosterically by ATP (activator) and dATP (inhibitor). Now crystal and EM structures of human and yeast ribonucleotide reductase 1 in complex with different nucleotides, together with mutagenesis and functional analysis, reveal how dATP binding induces hexamerization and consequence inhibition of the enzyme.

Binding of a neurotransmitter to the ligand-binding domain of glutamate receptors results in conformational changes and opening of the channel. The relationship between ligand binding and activation is not clear, and now the energetics of ligand binding are dissected using computational methods.

Riboswitches are RNA elements that provide feedback regulation of metabolic genes upon ligand binding. The glmS riboswitch is also a ribozyme, self-cleaving upon glucosamine-6-phosphate binding. By following intracellular self-cleavage under different growth conditions, it is now found that this riboswitch also responds to inhibitory metabolites, arguing that it integrates multiple signals in response to the metabolic status of the cell.

The formation of aggregates of polyglutamine (polyQ) sequences is initiated by nucleated growth polymerization. New results show that over a short repeat length range from Q26 to Q23 the size of the nucleus changes from monomeric to dimeric to tetrameric, suggesting aggregation nucleus size has a role in pathogenicity.

Genetic selection uncovers a novel periplasmic chaperone called Spy, whose expression is strongly induced by conditions that cause protein unfolding. Spy can suppress protein aggregation and promote refolding in an ATP-independent manner in vitro. The crystal structure of Spy reveals a thin, cradle-shaped dimer that might shield aggregation-prone regions exposed in unfolded substrates.

Complement factor H (FH) binds complement 3b and promotes the stepwise degradation of C3b to C3d, protecting self cells from being mistakenly recognized as foreign. A previous structure showed how CCP modules 1–4 of FH bind C3b; this study now shows the interaction of CCP modules 19–20 with C3d and builds a model for the interaction of the complete FH molecule with C3b.

Knowledge of the molecular mechanisms of activation of Clostridium difficile toxins will significantly enhance the ability to design specific anti-virulence therapies. Using activity-based chemical probes in combination with other techniques, this study reveals mechanistic insights into how inositol hexakisphosphate binding at the active site of the cysteine protease domain shifts the conformational equilibrium towards an active conformer.

Exportin-5 is involved in microRNA precursor nuclear export. Dicer mRNA is now found to compete with pre-miRNAs for exportin-5 binding, suggesting that cytoplasmic levels of Dicer and its pre-miRNA substrate engage in a feedback loop. Analysis of adenoviral RNA indicates that it can also compete for exportin-5, suggesting that this might be a mechanism by which adenovirus can interfere with host miRNA processing.