Volume 17 Issue 9, September 2010

The structure of the small heat shock protein αB-crystallin, associated with multiple sclerosis and Alzheimer's disease, has eluded biologists for years. Small angle X-ray scattering and solid-state NMR reveal a curved dimer that modulates substrate interactions upon a change in pH.

Adenosine deaminases acting on RNA (ADARs) catalyze hyper-editing of long dsRNAs, converting up to 50% of adenosines to inosine, to form IU-dsRNAs. Now IU-dsRNAs are shown to inhibit activation of IRF3 and suppress induction of interferon-stimulated genes and apoptosis, via specific binding to MDA-5 or RIG-I.

The activity of Retinoblastoma protein (Rb) is controlled by its phosphorylation status. Now the crystal structure of Rb in complex with the catalytic subunit of protein phosphatase 1 (PP1c) along with functional work reveals that the interaction site on Rb is also the target for Cdk-Cyclins, indicating that kinase and phosphatase compete for substrate docking.

The FUSE regulatory system, consisting of FBP binding the FUSE DNA element and recruiting the FIR repressor, acts as a transcriptional on/off switch that promotes a peak of c-myc expression over the course of a cell cycle. FIR recruitment and its interaction with FBP is now examined, providing a basis for precise c-myc transcriptional regulation.

Nuclear pores form post-mitotically but also during interphase and over the course of cell cycle, their number doubles as does nuclear volume. It is now shown that the appearance of new nuclear pores during interphase is cdk-dependent, though nuclear growth is not, suggesting that these two processes are regulated distinctly.

Ensuring the ribosome accepts a correct tRNA is key to fidelity of translation. The structures of the 70S ribosome carrying correct and incorrect tRNAs are now presented, giving mechanistic insight into the tRNA proofreading process where ribosomal proteins are shown to play an active role.

Trinucleotide repeat expansions are linked to many diseases, and why there are differences in expansion rates according to tissue type or patient age is unclear. Now an analysis of replication patterns in patient fibroblasts and transgenic mouse tissues carrying the human DM1 locus reveals how changes in modes of replication origin activation around the repeat can lead to expansions.

Toll-like receptor 2 is activated by triacylated lipoproteins, but structural and functional studies now show that Mycobacterium tuberculosis lipoprotein LprG is a TLR2 agonist even when it is non-acylated. LprG contains a hydrophobic pocket to bind triacylated glycolipids and delivers them to TLR2, perhaps via CD14. In addition, LprG may serve as a glycolipid chaperone in cell wall assembly by Mycobacterium tuberculosis.

Dcp2 mediated decapping of mRNAs is a key step in 5'-3' transcript decay. Using NMR-based analysis, it is now shown that the cap is recognized by two distinct regions in the regulatory and catalytic domains of Dcp2. This argues that cap recognition involves these regions coming together, in a step promoted by the regulatory factor Dcp1, thus leading to catalysis.

The fourteen members of the PYR/PYL family are receptors for the plant hormone abscisic acid (ABA). Now structural and functional work using the synthetic ligand pyrabactin, which inhibits seed germination, reveal that the PYL/PYR receptors respond differently to pyrabactin, elucidate the mechanisms for selective activation or inhibition of ABA receptors and allow the design of novel agonists.

The synthetic ABA agonist pyrabactin helped identify the PYR/PYL family of ABA receptors. Now the selectivity of pyrabactin toward specific members of this family is explained using genetic, chemical and structural approaches. Subtle differences in the binding pockets of the receptors lead to productive or nonproductive conformations upon pyrabactin binding.

PTB is a repressive splicing regulator. The effect of PTB knockdown in HeLa cells is now examined, indicating that similar to other recently examined factors, PTB variably affects splicing in a predictable fashion depending on where its binding site is relative to the target exon.

AID is a DNA cytidine deaminase with a central role in the generation of antibody diversity. AID initiates class switch recombination by modifying DNA within the switch (S) regions in the IgH locus. Now AID is shown to be targeted to the S regions by interaction with adaptor proteins 14-3-3, which in turn bind directly to the DNA motif 5'AGCT.

The function of GenX, an aminoacyl-tRNA synthetase paralog in Escherichia coli, is now probed by structural and functional analyses. The work shows that GenX mediates the lysylation of translation elongation factor EF-P, and this activity is essential for cell growth.

How changes in chromatin can modulate the repair pathway of DNA double-strand breaks is now investigated. The work shows that histone deacetylases HDAC1 and HDAC2 are recruited to sites of DNA damage, where they mediate the removal of H3K56 acetyl marks, and their activity is important for repair via non-homologous end-joining.

The structure of Moxifloxacin, a quinolone antibacterial, in complex with Acinetobacter baumannii topoisomerase IV and DNA now shows how the drug stacks between base pairs at the DNA cleavage site. Moxifloxacin contacts the protein through a non-catalytic Mg²⁺, and the structure gives insight into the mode of inhibition and possible basis of drug resistance.

RNA polymerase II is post-translationally modified on its C terminal domain and these modifications have been associated with different states of Pol II transcription. These modifications are now examined at a genome-wide level, and chemical inhibitors are used to argue that promoter-distal Ser7P is specifically placed anew by the Bur1 kinase.