News & Views

A detailed quantitative model of signaling by IRE1 sheds light on the mechanism of its activation by endoplasmic reticulum stress and addresses a long-standing controversy in the field.

To cope with the life-threatening crisis of a DNA interstrand cross-link (ICL), human cells must invoke the Fanconi anemia (FA) DNA repair pathway. The FA pathway is a multistep repair process, requiring multiple nucleolytic incisions and translesion DNA synthesis. Recent work from four laboratories has identified a novel FA-associated nuclease, FAN1, that binds directly to monoubiquitinated FANCD2, resolving a decade-long puzzle regarding the function of this FANCD2 modification.

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.

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.

Crystal structures of a calcium-dependent protein kinase from Toxoplasma gondii uncover a unique mechanism of activation and potential avenues for selective inhibition.

In this issue, three papers report the distribution of the RNA polymerase III (Pol III) machinery, including transcription factor IIIB, transcription factor IIIC and Pol III itself, across the human genome. These studies reveal cell type–specific expression of Pol III genes, functional interplay between the Pol II and Pol III transcriptional machineries and the potential involvement of Pol III genes in chromosome organization.

A new crystal structure of an anti–HIV-1 envelope antibody bound to an envelope–receptor complex shows the antibody binding both the HIV-1 envelope and the CD4 receptor, raising the question of what the role of antibody autoreactivity in host responses to HIV-1 may be.

The tumor suppressor p53 protects the cell from cellular stress, and in so doing it decides between cell-cycle arrest and cell death. The high-resolution structure of four DNA binding domains of p53 in complex with DNA shows how the structural collaboration between protein and DNA may influence the biological outcomes of the tumor suppressor.

Eukaryotic cells have numerous non–membrane bound bodies whose functions are often unclear. On page 403 of this issue, Strzelecka and colleagues provide evidence that the ability to form Cajal bodies increases the rate of small nuclear ribonucleoprotein (snRNP) biogenesis and/or function. This supports the hypothesis that some cellular bodies form to increase the rates of assembly of multicomponent cellular machines.

Two recent papers break major new ground on the issues of NHEJ, backup pathways for NHEJ and how these relate to the chromosomal translocation process.

In this issue, a long-awaited report sheds new light on the strange performance of bacterial flagellar filaments. We now have high-resolution data on two different, 'switched' versions of the structure.

Synaptotagmins and SNAREs are known to couple Ca²⁺ sensing to membrane fusion during Ca²⁺-triggered exocytosis, but unraveling the mechanism of this coupling has proven extremely difficult. Two studies in this issue now provide crucial insights into the nature of synaptotagmin-SNARE interactions and reveal unsuspected similarities between synaptotagmins and viral fusion proteins.

Myotonic dystrophy is caused by expanded CTG repeats, and the expression of these repeats as RNA leads to the sequestration of the splicing factor muscleblind-like (MBNL1) to the CUG RNA. Two mouse models for myotonic dystrophy—mice expressing expanded CUG repeats and mice lacking functional MBNL1—now reveal ∼100 new mis-splicing events and a new class of aberrantly regulated mRNAs.

γ-secretase cleaves multiple substrates with essential roles from development to neurodegeneration, and its aberrant processing underlies human disorders including Alzheimer's disease (AD). Tian et al. now identify a domain in the β-amyloid precursor protein (APP) that inhibits γ-secretase activity and show that certain familial AD–linked APP mutations within this domain impair this inhibition, resulting in increased β-amyloid generation. The study thus reveals a novel mechanism whereby γ-secretase's activity is influenced by its own substrate.

An X-ray crystal structure of an organic anion transporter identifies it as an ion channel instead. Its similarity to an unrelated family of water channels raises evolutionary questions that have been recently bubbling up around membrane proteins.

Chromosome end protection is accomplished by telomeres. How cells cope with spontaneously unprotected telomeres while avoiding cell cycle arrest or cell death is a fascinating question.

Flu viruses package essential functions into a small integral membrane protein known as M2. Such small membrane proteins represent major challenges for structural biology. A new study presented in this issue details the structure and functions of the influenza B M2 protein through the use of functional domain–specific solution NMR spectroscopy.