Volume 17 Issue 6, June 2010

In this issue, Ishikawa and colleagues provide direct evidence to support the 'winch' hypothesis for the dynein motor mechanism, in which the AAA domain motor unit is displaced parallel to the doublet microtubule long axis rather than undergoing a rotary motion.

Stringent post-transcriptional regulation of the amyloid precursor protein (APP) is critical for maintaining proper neurological function. In this issue, Lee et al. identify two RNA-binding proteins, FMRP and hnRNP C, that have opposite effects on APP translation via competing interactions, surprisingly, with the mRNA coding region.

The signal recognition particle (SRP) has evolved in chloroplasts to include new components, new ways of recognizing targeting substrates and new capabilities that prevent aggregation of protein-targeting substrates or even rescue substrates from an aggregated conformation. Unique attributes of chloroplast SRP are focused toward localizing a single family of nuclear-encoded chlorophyll-binding proteins to thylakoid membranes and suggest that the successful migration of this gene family to the nucleus was tied to evolutionary adaptations in chloroplast SRP.

During spermatogenesis most histones are replaced with protamines. The distribution of the products of Trithorax and Polycomb histone modifications are now examined in both mouse and human sperm, showing conservation of histone methylation distribution across species. The authors propose a role for the Polycomb complex in transgenerational inheritance.

A transposon mutagenesis screen indicates that loss of 53BP1 expression rescues the clonal growth defect of BRCA1 null cells. 53BP1 deficiency is shown to abrogate the cell cycle arrest triggered in the absence of BRCA1 and to partially restore homologous recombination. The potential clinical implications of these findings are supported by the reduction of 53BP1 expression in sporadic triple-negative and BRCA-associated breast cancers.

Membrane proteins require chaperones to keep them soluble and translocation-competent. New studies have identified a chloroplast signal recognition particle, cpSRP43, as a highly specific, ATP-independent chaperone that efficiently reverses aggregation of its substrate proteins by specific binding interactions between the chaperone and its substrate.

The Drosophila fs(1)K10 transcript is localized asymmetrically during oogenesis through a cis-acting RNA element called the TLS. The tertiary structure of this hairpin is now presented, and while it contains W-C base pairs, the RNA helix takes on an A' form conformation that is needed for correct subcellular targeting.

Membrane fusion proceeds via the distinct stages of docking, hemifusion and fusion pore opening, which requires the coordinated actions of Rab, SNARE and SM proteins. Studies with yeast vacuoles now reveal that the SM protein Vps33 promotes fusion pore opening by enhancing the fusogenic activity of a SNARE complex, suggesting that SM proteins may be integral parts of the membrane fusion machinery.

The Hedgehog signaling pathway is implicated in a number of cancers, and synergism with the RAS pathway has been suggested. Now the molecular mechanisms of this interaction are uncovered, revealing that oncogenic RAS shifts Hedgehog signaling to a paracrine mode via its effector kinase DYRK1B.

RET tyrosine kinase is essential for various developmental processes, and loss-of-function ret missense mutations cause Hirschsprung's disease (HSCR). Structural studies identified residues that constitute a crucial folding bottleneck relevant to the maturation of RET in the endoplasmic reticulum, and the maturation efficiency of ret mutants correlates well with their severity in patients with HSCR disease.

Amyloid precursor protein (APP) is implicated in synapse formation and synaptic plasticity and its cleavage product Abeta has been linked to Alzheimer's disease. New evidence suggests that the RNA-binding proteins hnRNP C and FMRP have opposite regulatory effects on APP translation, and that repression of APP translation correlates with colocalization of FMRP and tagged APP RNA in processing bodies.

RNase Ps are involved in tRNA maturation and are typically found to be ribonucleoproteins. An essential Arabidopsis thaliana organellar protein is now found to possess RNase P activity and be able to replace the E. coli ribonucleoprotein RNase P.

Previous studies have indicated that the nucleosome poses a barrier to the passage of RNA polymerase. It is now shown that a trailing bacterial RNA polymerase can reduce backtracking and enhance the movement of a leading polymerase through the nucleosomal barrier.

While activators must impact the Mediator complex to promote transcription, the mechanisms that underpin this are currently unclear. The effects of p53 domain-binding on transcription and mediator structures now argue that a pocket, similar in size to one previously seen upon SREBP binding, may be a feature of an activated Mediator complex.

Eukaryotic flagella and cilia contain at their core microtubules that slide against each other to produce a bending motion. The movement is powered by dynein molecules associated to the microtubules. Now an in situ cryo-electron tomography analysis of Chlamydomonas reinhardtii flagella reveals the global conformational changes induced by nucleotides in the outer and inner dynein arms.

Membrane proteins pose a huge challenge for structural analysis, but a new study reports the first NMR structure determination of a detergent-solubilized seven-helical transmembrane (7TM) protein, the phototaxis receptor sensory rhodopsin II. This case study may open the doors to similar solution NMR structures for other 7TM proteins.

While the topological analysis of protein complexes by electron microscopy (EM) has developed in recent years, the exact position of single subunits within multisubunit complexes has been difficult. A new clonable peptide tag, which when attached to a target protein can recruit a structurally prominent label that is easily identifiable by EM, may help solve this problem.

Nature Structural & Molecular BiologyandNature Reviews Molecular Cell Biologyhave teamed up to present an in-depth joint Focus on Signal Integration, with specially commissioned Reviews in each journal. These articles consider some of the key approaches used to study signaling networks, and discuss how various signals are integrated in different cellular contexts.