Volume 9 Issue 11, November 2013

NAD⁺-dependent deacetylases of the sirtuin family have long been implicated in lifespan regulation, and the significance and molecular mechanism (or mechanisms) of this effect have engendered spirited debate. Two articles now spotlight the catabolism of NAD⁺ itself as a mediator of lifespan regulation.

The nicotinic acetylcholine receptor (nAChR) is regulated by changes in the host lipid bilayer composition and has been studied extensively to elucidate the relative importance of specific lipid-protein interactions versus more general nonspecific bilayer-protein interactions in the regulation of membrane protein function. Experiments reported in this issue provide strong support for the importance of lipid bilayer physical properties and lipid bilayer–membrane protein hydrophobic mismatch in the regulation of nAChR function.

Large-scale cell line profiling of drugs provides dose-response curves that contain numerous lesser-considered parameters. Understanding the reasons for systematic variation in these parameters offers new ways to compare drugs and potentially to guide improved drug profiles.

Cytoplasmic polyadenylation activates quiescent transcripts for translation by selective poly(A)-tail extension. An approach involving a clickable adenosine derivative permits capture of newly polyadenylated transcripts, and next-generation sequencing reveals mRNA sequence motifs that are linked to polyadenylation.

Aspartate is a primary nitrogen source for Mycobacterium tuberculosis during infection, being required for virulence after entering cells via the amino acid transporter AnsP1.

Specific inhibitors against Hsp90 paralogs show that Hsp90 and Grp94 regulate HER2 in a cell-specific and proteome alteration-driven manner.

Polyketide synthases infrequently insert β-branched monomers into their growing polyketide chains, the details of which are not well established. Bioinformatic, structural and mutational analyses now define a core motif and surface residues in acyl carrier proteins that govern insertion of β-branched units.

Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.

Membrane hydrophobic thickness modulates transitions between uncoupled and coupled nAChRs by a kinetic mechanism.

IC₅₀ values are widely used measures of compound potency. A multiparametric analysis of dose-response curves derived from a panel of cell lines treated with anticancer drugs reveals that there can be systematic variability in dose-response parameters across drug classes and cell types, effects that are not apparent by inspection of IC₅₀ values.

The anesthetic propofol binds in a cavity on the β subunit of the GABA_A receptor between the transmembrane and extracellular domains, near other residues that have been shown to be important for determining anesthetic sensitivity.

A 'lockdown' mechanism explains why the CLC-ec1 Cl⁻/H⁺ antiporter is selective against F⁻ ions, whereas Cl⁻ and other inorganic ions are moved indiscriminately.

Isolation and characterization of the first hydroxyproline O-arabinosyltransferases demonstrates overlapping and distinct functions in glycosylating protein substrates and controlling plant development.

Phenotypic screening using a reporter for Notch trafficking and processing leads to the identification of five compounds that affect this pathway, including one that acts at a pre-ER exit step in a manner distinct from known molecules.

Crystal structures of α-L-iduronidase, the enzyme linked to MPS I, now provide snapshots of the catalytic pathway and rationalize the role of 100 disease-related mutations, while biochemical analysis of deglycosylated and mutated enzymes define roles for non–active site residues in controlling function.