News & Views in 2011

Concern over exposure to the radioactive fallout from nuclear power generation is episodic; not surprisingly, it is heightened at present, following the tragedy in Japan. A primary cytotoxin cohort released in such reactor meltdowns consists of isotopes of plutonium (Pu), all radioactive. The most common valence form, Pu(IV), mimics Fe(III) in the transferrin–transferrin receptor pathway; this pathway serves as Pu's 'Trojan horse' through which to enter the body.

Bacteria communicate by sending and receiving chemical cues in a process termed 'quorum sensing'. New research shows how five feedback loops of the Vibrio harveyi quorum sensing cascade ensure signal integration and transmission fidelity, with one loop controlling signal sensitivity by regulating receptor ratios.

A potent and selective inhibitor for the protein lysine methyltransferases G9a and GLP has been discovered. This small molecule serves as a useful probe to decipher the specific role of these enzymes in the development of various diseases.

Peptide agonists of class B G protein–coupled receptors have separate segments for binding and activation. Synthesizing peptidic analogs that can be 'clicked' together allows for rapid optimization of agonist activity—as well as providing some surprises about receptor pharmacology.

Phosphomimetic mutations at huntingtin (Htt) Ser13 and Ser16 within the conserved N-terminal 17-amino-acid domain profoundly suppresses its toxicity in cell and mouse models of Huntington's disease. New research reveals that cell stress acts as a stimulus for double phosphorylation of endogenous Htt, causing its nuclear translocation, and shows that certain chemicals can target such molecular processes in Huntington's disease cell models.

Metabolic engineers have long sought a rational approach to designing hybrid organisms with unique biosynthetic capabilities. Combining in silico pathway discovery with genome-scale modeling has now provided an engineered Escherichia coli capable of producing the unnatural fermentation product 1,4-butanediol at near-commercial levels.

The combination of NMR spectroscopy and statistical mechanics represents a powerful approach to characterize the behavior of macromolecules. Two recent studies demonstrate that the application of this strategy to analyze chemical shift measurements can reveal complex mechanisms of protein regulation.

Spiroacetal substructures introduce important conformational constraints into bioactive polyketide natural products. New research reveals a two-enzyme team responsible for this molecular origami in reveromycin A biosynthesis.

Bacteria oscillate between the planktonic and biofilm states through many hierarchically organized networks that respond to environmental cues. Recent research describes how a bacterial toxin-antitoxin system mediates this transition by controlling bacterial motility in response to extracellular stress.

Riboswitches are so named because they switch gene expression on or off in response to binding of specific metabolites. Two evolutionarily and mechanistically divergent riboswitches that recognize the universal methyl donor S-adenosylmethionine are shown to undergo dynamic conformational sampling before ligand binding.

STIM proteins are ubiquitous endoplasmic reticulum Ca²⁺ sensors that rapidly translocate to couple with 'store-operated' Orai Ca²⁺ channels when luminal Ca²⁺ levels are low. STIM1 also senses heat changes, which trigger a similar translocation and prime STIM1 to activate Orai, suggesting that STIM1 functions as a sensor of multiple stress signals.

Directed evolution of nucleic acids and proteins in the laboratory can produce many novel phenotypes in a relatively short time frame. A significant enhancement to these techniques allows continuous evolution in special turbidostats and can speed the discovery of proteins with desirable activities.

Classical cannabinoid receptors do not mediate all actions of the active drug in cannabis, THC. Here the mechanism by which THC enhances glycine receptor activity has been identified and used to design new pain therapeutics that avoid THC's adverse effects.

A small subpeptide from the tumor suppressor p53 is shown to mediate aggregation that is similar to that of amyloids. The result is nucleated assembly by mutant p53 that can abrogate function of wild-type p53 and its two functionally important homologs.

Parathyroid hormone analog PTH(1–34), used clinically to treat osteoporosis, forms a stable complex with its receptor and prolongs cAMP production even after internalization and recruitment to endosomes. New data suggest this signaling cascade is stimulated by β-arrestins and terminated by retromer.

High-throughput screening in Caenorhabditis elegans identified a compound that distinctly regulates fat storage and feeding, highlighting new players in energy homeostasis.

Detailed biophysical and biochemical studies provide an exquisite example of how conformational flexibility controls the interaction between an intrinsically disordered protein and its numerous binding partners.

Amorphous mineral phases play important roles in the skeletons of many organisms, but the molecular basis for species-specific control is still under debate. The demonstration that energy-rich metabolites such as phosphoenolpyruvate stabilize amorphous calcium carbonate (ACC) in crayfish inspires speculation about calcium minerals in emerging metabolisms.

The assembly of chimeric synthetic pathways in cell factories will enable production of novel fuels and chemicals by microbial fermentation. The assembly of five enzymes for production of 1-butanol in Escherichia coli using kinetic considerations provides new lessons regarding these endeavors.

O-GlcNAc transferase is an essential protein catalyzing the O-GlcNAc modification of hundreds of intracellular proteins in higher eukaryotes. The structure of human O-GlcNAc transferase represents a leap in our understanding of the catalytic mechanism and recognition of protein substrates.