Articles in 2008

Pirh2 is one of several ubiquitin ligases known to modify and negatively regulate p53. Solution studies reveal the structures of the three Pirh2 domains and indicate that the C-terminal domain of Pirh2 interacts with the p53 tetramerization domain. Additional data suggest that Pirh2 preferentially modifies the tetrameric, transcriptionally active form of p53 for proteasome-mediated degradation.

The MSL complex is involved in upregulation of genes on the Drosophila melanogaster male X chromosome during dosage compensation. Using mutagenesis, the MSL3 chromodomain is now shown to interact with methylated histone H3K36 and is implicated in the spreading of the dosage-compensation complex from its initial binding sites, defining a process of spreading by activation complexes analogous to that defined for silencing complexes.

Bag2 acts as a nucleotide-exchange factor for Hsp70 and also binds misfolded substrates. Now structural work reveals that Bag2 promotes nucleotide exchange via a mechanism distinct from other Hsp70 nucleotide-exchange factors, and mapping of the binding sites for client peptides suggests how Bag2 assists Hsp70 in processing misfolded proteins.

The ATP-dependent chromatin-remodeling complexes are involved in repositioning, evicting and restructuring nucleosomes. The EM reconstruction of the RSC remodeler in complex with a nucleosome gives structural insights into remodeling.

The replication of many retroviruses depends on interactions between the viral TAR RNA element and Tat as well as Cyclin T1, a component of the cellular transcriptional elongation complex. Structural insights into this ternary complex now suggest that the equine infectious anemia virus TAR is engaged by both proteins with Tat in a helical conformation and that binding depends on flipping out specific bases in the TAR loop region.

F1 ATPase contains three catalytic β subunits that hydrolyze ATP, causing the central γ subunit to rotate. Now, using fluorescent tags, conformational changes in β and rotation of γ are observed simultaneously within the same complex, allowing the motions in β to be correlated with catalytic events and ultimately rotation.

Understanding the kinetics of gene expression involves accurate quantitation of gene expression. This is now undertaken by quantifying nascent-RNA levels and relating this indication of transcriptional activity to mRNA abundance in single yeast cells. Combining these measurements with computational modeling indicates that the tested yeast housekeeping genes are probably expressed through single initiation events, whereas a SAGA-transcribed gene shows behavior consistent with transcriptional bursting.

Oxidative stress can lead to cellular senescence, in a p53-dependent pathway. Bach1, a transcription factor that regulates the response to oxidative stress, is now shown to inhibit senescence induced by high oxygen concentrations or by Ras. Bach1 is recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation.

The interactome of eukaryotic chaperonin TRiC/CCT is identified through a genome-wide approach, revealing an enrichment in large, multidomain proteins, or components of multimeric complexes, rich in hydrophobic sequences and with high β-sheet propensity. Thus, TRiC substrates are slow-folding proteins with complex topology, which are likely to be more prone to aggregation.

Emerging evidence suggests that ESCRT proteins, well characterized in their role in multivesicular body trafficking, contribute to various cellular processes including cytokinesis. Structural and functional analyses indicate that the ESCRT-III protein CHMP1B promotes the midbody localization of spastin, a microtubule-severing protein required for membrane abscission.

The IpaH family of Shigella virulence factors are E3 ubiquitin ligases that may target host proteins. Structural and functional characterization of IpaH1.4 and IpaH9.8 reveal a unique C-terminal catalytic domain that seems to have HECT-like E3 ligase activity. Together with an accompanying publication from Zhu et al., these data suggest that the IpaH proteins constitute a new category of ubiquitin ligases.

The IpaH proteins from Shigella show ubiquitin-ligase activity but lack obvious sequence similarity to HECT- or RING-type ubiquitin ligases. The crystal structure of IpaH3 reveals a two-domain protein with HECT-like catalytic activity mapped to a C-terminal domain of novel fold. These findings suggest that IpaH proteins represent a new family of ubiquitin ligases, a conclusion supported by results from a related study by Tyers et al.

This year's Nobel Prize in Chemistry recognized the researchers whose work literally illuminated biological processes.

Much has been written and said about the links between the Ink4a-Arf locus, cellular senescence and stem-cell maintenance. Standing modestly in the shadows of these superstars of tumor suppression, the closely linked Ink4b gene is now emerging as a significant player in these events, and its regulation by a histone demethylase could provide new insights into how this remarkable locus is controlled.

In this issue of Nature Structural & Molecular Biology, work on the bacterial AAA+ machine ClpX provides insight into how the ATPase subunits exert a translocating force on their substrates.

The open gate of the BK-type K⁺ channel is stabilized when the voltage-sensor domains (VSDs) are activated by depolarization and the intracellular Mg²⁺ sensors are occupied. A systematic investigation reveals that each Mg²⁺ is bound by the transmembrane VSD and cytoplasmic ligand-sensing domain from two adjacent subunits, suggesting that relative positions of sensor and gate domains of BK channels may differ substantially from those suggested by homology models.

The Fanconi anemia pathway is part of the DNA-damage network including breast cancer–susceptibility proteins BRCA1 and BRCA2. This pathway is activated by the ataxia telangiectasia and Rad3–related (ATR) kinase, but the underlying mechanism remains unclear. A new study demonstrates that a major switch activating the pathway is the ATR-dependent phosphorylation of FANCI.

Group II introns are retroelements that have invaded the genomes of many prokaryotes and eukaryotes. The structure of a self-spliced group IIC intron cocrystallized with ligated exons (the target substrate) reveals the metal ions that have a role in catalysis and the intron sequences that are important in exon recognition in group II introns.

Most known nucleotidyl-transfer enzymes use two metal ions for catalysis, but some enzymes use only one divalent cation in their active sites. A comparative analysis of previously available structural data reveals that the one-metal-ion enzymes use a similar mechanism to coordinate their single metal ion, which corresponds, functionally and structurally, to metal ion B in the two-metal-ion enzymes.