Articles in 2012

AID/APOBEC deaminases, which convert cytosine bases to uracils in DNA and RNA, have recently been assigned a role in epigenetic regulation as components of DNA demethylation pathways. A systematic study shows that AID/APOBEC enzymes preferentially deaminate unmodified cytosine over its C5-modified forms, calling into question the plausibility of deaminase-mediated DNA demethylation pathways.

Hydrogen sulfide anion reacts with cellular electrophiles, including 8-nitro-cGMP, and sulfhydration products inhibit S-guanylation–dependent H-Ras activation in cardiac inflammatory injury models.

The chaperone FimC only selects unfolded, disulfide-intact pilus subunits and accelerates protein folding by lowering topological complexity, thereby ensuring quality control in pilus assembly.

Different key residues mediate melanocortin-4 receptor activation via the agonist αMSH or constitutive activation via interaction of the transmembrane domain with the N-terminal domain, and these modes are further distinguishable by the different effects of the physiological antagonist.

Phenylketonuria (PKU) is characterized by increased levels of phenylalanine in the blood and progressive mental retardation. Now, phenylalanine is shown to form toxic amyloid fibrils at high concentrations, which accumulate in the brains of PKU patients and mouse models.

Phage display reveals peptides that bind to the caspase-6 zymogen, inducing its tetramerization and specifically inhibiting its enzyme activity both in vitro and in neuronal cells.

Fluorinated, cell-permeable analogs of sialic acid and fucose are processed by monosaccharide salvage pathways to generate sialyl- and fucosyltransferase inhibitors intracellularly. These compounds serve as important new tools to dissect the role of glycan modifications within complex biological systems.

A genetic synthetic lethal screen reveals that ATM and MET kinases promote cell survival upon activation of p53 with Nutlin-3, and these survival pathways act in parallel to canonical cell cycle arrest and apoptotic genes induced by p53.

A computational screen identifies a small-molecule activator of proapoptotic BAX that selectively binds to the BAX trigger site, inducing characteristic conformational changes, oligomerization and BAX-dependent cell death.

The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα_i/o, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.

The first crystal structure and in vitro biochemical characterization of an enoylreductase domain from a multimodular polyketide synthase indicates substantial architectural deviations from the mammalian fatty acid synthase and identifies an active site residue that controls catalytic activity.

BRET probes that monitor activation of multiple G protein isoforms reveal that angiotensin II and a biased agonist of the angiotensin II type 1A receptor stabilize distinct receptor conformations associated with different signaling outputs.

NMR structures of CrkL, an adaptor protein that mediates Bcr-Abl signaling in CML, reveal domain organization distinct from CrkII that allows constitutive interaction between CrkL and Abl kinase.

Brassinosteroids (BRs) are plant growth hormones that bind the brassinosteroid receptor (BRI1) and activate its kinase domain. Exploration of BRI1-BR trafficking using a fluorescent brassinosteroid probe alongside chemical and genetic tools reveals that endocytosis pathways are essential for BR signaling attenuation and BRI1 turnover.

A chemoproteomic approach adapted for high-throughput screening leads to the identification of a selective PI3Kγ inhibitor. Application of this inhibitor in human and mouse cellular models reveals a role for PI3Kγ in T_H17 cell differentiation.

Cyclodehydrations in thiazole/oxazole-modified microcin biosynthesis are known to require a multiprotein complex, but full details of the reaction were not clear. Substrate analogs and isotopic labeling now show the D protein, thought to serve a scaffolding function, catalyzes ring formation and uses ATP to activate the substrate.

Bacteria must control their metabolism to quickly adapt to changing carbon sources. PEP carboxylase is now shown to be allosterically regulated by fructose-1,6-bisphosphate in an ultrasensitive manner, turning glycolysis on and off almost instantaneously in response to glucose availability.

Trp-tRNA synthetase (TrpRS) has a well-understood role in translation by facilitating aminoacylation of Trp-tRNAs. The discovery of a nuclear signaling role for TrpRS as a bridging protein for DNA-PK and PARP-1, resulting in p53 activation, explains a previously curious link between interferon-γ signaling and concomitant TrpRS overexpression.

Antisense oligonucleotides (ASOs) are widely used to modulate gene expression through sequence-specific duplex formation with target RNAs. ASOs containing specific 2′-fluorine substitutions are shown to recruit ILF2/3 to pre-mRNA and induce exon skipping in cells and in mice.

The diperpenoid adenanthin covalently modifies the resolving cysteine from peroxiredoxins to inhibit the reduction of hydrogen peroxide, a second messenger in cells, and thereby activates pathways that promote the differentiation of leukemia cells.