Volume 7 Issue 12, December 2011

The research community lost one of its finest members when Chris Raetz succumbed to cancer in August. Through his research and training of more than 30 students and 40 postdoctoral fellows, Chris made an indelible and lasting mark on many in the lipid biochemistry community both personally and professionally.

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.

By seeking to replicate either specific biochemical reactions or the chemical logic employed by cellular machinery, biomimetic synthesis serves to both inform and test proposals for natural product biosynthesis as well as expand and redefine the rules of organic chemistry.

The large number of available chemical strategies to modify biomolecules can be overwhelming and time-consuming if adopted without careful consideration. Applying chemical logic to select context-dependent protocols can streamline this process substantially, leading to a wealth of functionalized materials for use in biology and materials science.

N6-Methyladenosine is an abundant nucleoside in cellular mRNA that undergoes demethylation under physiological conditions by fat mass and obesity-associated protein (FTO). This new pathway suggests that RNA modifications can be reversible and potentially have an impact on RNA metabolism.

Cleavage of peptide precursors is well known for ribosomally produced sequences. Investigation of xenocoumacin biosynthesis now points to a similar function in nonribosomal peptide synthesis clusters, explaining one source of mismatches between genetic and chemical information.

Dafadines, identified in a screen for compounds that induce the dauer phenotype in C. elegans, also promote longevity in adult worms, with both phenotypes occurring through inhibition of DAF-9, a cytochrome P450 involved in the insulin signaling pathway.

Cells must coordinate nutrient uptake for balanced growth, but the mechanism by which this occurs was unknown. Flux measurements and biochemical assays now identify α-ketoglutarate as the key signal in this process that accumulates upon nitrogen limitation and inhibits an enzyme involved in glucose transport.

An evolutionary algorithm predicts anti-inflammatory drug combinations that have synergistic effects on IL-1β expression more efficiently than would empirical approaches of testing drug combinations individually.

GPCRs are known to initiate a variety of signaling pathways, but their full reach in coordinating cellular events is unknown. Live cell imaging using label-free and fluorescence assays to monitor the effects of GPCR ligands now surprisingly connects GPCR networks to nucleotide metabolism.

NMR and ITC are used to define essential features of a p38α phosphatase interface that extend beyond the classic KIM binding site, and SAXS analysis software, incorporating NMR chemical shift data, are developed and applied to build a model of the p38α-HePTP complex.

Conformation-specific antibodies and longitudinal tracking of individual neurons in situ identifies a toxic monomer species linked to Huntington's disease.

Coiled-coil assemblies have served as a rich resource for testing fundamental principles of protein structure and function. A semi-empirical design strategy now yields the first parallel hexamer, which also displays an internal channel that can be manipulated to direct assembly.

Trafficking G proteins between membranes is essential for their signaling activity. Structural and biochemical studies on the farnesylated G protein Rheb and the guanine nucleotide–dissociation inhibitor (GDI)-like PDEδ suggest an allosteric mechanism for Rheb release and identify a bona fide GDI-displacement factor (GDF).

IMPDH and GMPR have similar active sites, but their reactions cause opposite effects on the guanine nucleotide pool. Biochemical and crystallographic evidence point to cofactor conformation as distinguishing the two reaction mechanisms and demonstrate that GMPR can substitute for IMPDH, prompting further investigations of this metabolic cycle.