News & Views in 2011

Lysophosphatidic acid, a lipid mediator, second messenger and intermediate in lipid biosynthesis, finds a new intracellular target in TRPV1. This nonselective cation channel is also targeted by the analgesic capsaicin, which acts to desensitize the channel.

The multisubunit DNA polymerases of eukaryotes have iron-sulfur centers that are crucial for polymerase assembly and therefore the integrity of the nuclear genome.

Amino acids not only are useful for protein synthesis but also act as regulators of gene expression. An elegant genome-wide approach now shows how binding of amino acids to transcription factors regulates an integrated network of amino acid metabolism to suit the physiological needs of bacterial cells.

Designed expansion of hydrophobic contacts converts a coiled-coil tetramer to a true hexamer, a new protein fold previously deemed unlikely to exist. The complex has a central channel sized to allow passage of water molecules.

Cell membrane–bound G protein–coupled receptors are traditionally thought to stimulate cell proliferation by addressing the nuclear replication machinery, but we now learn that they also activate cytosolic nucleotide factories, the purinosomes.

The monoclonal antibody 3B5H10 that recognizes diffuse mutant huntingtin predicts cell death in primary striatal neurons. Biochemical and biophysical analyses reveal that the 3B5H10 epitope is exposed in a monomeric state, identifying this specific conformation as a toxic agent in Huntington's disease.

Proteins binding to lipid moieties of GTPases can extract the GTPases from membranes. An innovative study shows that Arl2 and Arl3 act as dissociating factors that allosterically squeeze the lipid moiety of a GTPase from the grip of a lipid-binding protein, thereby facilitating reincorporation of the GTPase into membranes.

For years scientists have debated whether glycans, like DNA, RNA and proteins, have a true sequence. In a recent study, researchers show that the proteoglycan bikunin has a defined and predictable sequence, opening the door for a new understanding of the glycome.

The first selective inhibitor of monogalactosyldiacylglycerol (MGDG) synthase was identified from a chemical library screen. The competitive inhibitor effectively targets MGDG concentrations across plant tissues and was used to demonstrate a new role for galactolipids in pollen-tube development.

Crystal structure and drug pharmacophore structure-activity data guided a combined mutagenesis and chemical screen to develop ligand-gated ion channels activated by unique chemical agonists. Through genetic engineering, these channels can be used to manipulate neuronal excitability and dissect the neuronal circuitry responsible for complex behaviors.

The extent to which ligand-free GPCRs exist in quasi-stable 'precoupled' complexes with G proteins in vivo is uncertain. New research, using fluorescence recovery after photobleaching (FRAP), reveals a structural requirement for and functional consequences of muscarinic acetylcholine receptor–G_q protein preassembly.

Monitoring oxygen (O₂) levels is essential to optimizing aerobic metabolism and ensuring proper biological processes in most eukaryotes. The spice chemosensor TRPA1 is a previously unidentified O₂ sensor in the mammalian sensory nervous system that warns against hyperoxia and hypoxia.

A recent flurry of activity has defined the protein FLOWERING LOCUS T (FT) as a mobile signal or 'florigen' that induces flowering. A new study has shown that a 14-3-3 protein links FT to a transcription factor at the plant apex to initiate flowering.

The glycosyltransferase-catalyzed generation of sugar nucleotides is normally an unfavorable endothermic process. Simple reactive glycosides used in conjunction with mutant transferases enable such reactions to become favorable exothermic processes, providing practical access to a diverse range of non-natural sugar nucleotides.

Purine riboswitches have served as models for riboswitch structure, dynamics, evolution and engineering. New crystallographic models reveal the adaptability of a purine riboswitch evolved to bind 2′-deoxyguanosine and highlight challenges inherent to riboswitch engineering.

A combination of chemical and genetic approaches has established a proof of concept in mouse models—with strong mechanistic underpinning—indicating that targeting the aberrantly recruited histone methyltransferase activity of DOT1L has therapeutic potential in aggressive leukemias driven by MLL fusion genes.

Man-made adhesives cannot match the ability of a marine mussel to affix itself to a wet rock. New insights help to describe the protein-surface bonding central to this feat of biological materials engineering.

Protein misfolding, oligomerization and aggregation are implicated in a variety of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. New research sheds light on the process of amyloid-β aggregation in vitro, identifying nucleated conformational conversion of oligomers as the mechanism for generating amyloid fibrils.

Nature's approach to biosynthesis often involves the rapid generation of advanced, enantiopure intermediates from simple starting materials. A new, highly efficient strategy adapts this approach, using organocascade catalysis to quickly construct a key intermediate that can be converted into several complex natural products.

Homo- and heterodimerization of G protein–coupled receptors (GPCRs) have been described for numerous receptors, but their functional role has remained elusive. With a new spectroscopic assay based on protein fragment complementation, GPCR heterodimerization was demonstrated to contribute to a phenomenon called 'functional selectivity'.