News & Views

The proteins that 'pump' neurotransmitters into neurons, clearing the synapse after a nerve impulse, are central players in coherent brain function and are targets of many psychotropic drugs. Two groups now endeavor to resolve a fundamental controversy about how these proteins work. The results shed new light on the controversy but do not end it.

Is there upregulation of the single active X chromosome in mammals or not? Recent studies take different points of view.

Structural studies of the epidermal growth factor receptor (EGFR) have advanced greatly in recent years, but they have used a 'divide-and-conquer' approach for independent study of the intracellular and extracellular regions. Several recent papers provide important new perspectives on 'undivided' EGFR and describe the initial steps in reconstructing signaling behavior of the intact receptor.

Oncogene-induced replication stress and DNA damage are among the hallmarks of cancer. A recent study explores how different levels of replication stress affect animal development and tumorigenesis, and how targeting of the replication stress–signaling pathway of ATR and Chk1 kinases can be exploited for selective killing of cancer cells.

The mammalian mitochondrial transcription factor A (TFAM) is encoded in the nucleus and imported into mitochondria, where it functions as an activator of mtDNA transcription and packages mtDNA into DNA-protein aggregates called mitochondrial nucleoids. Two studies in this issue reveal that TFAM shapes mtDNA into a sharp U-turn, providing a molecular mechanism for its dual roles in the expression and maintenance of mtDNA.

The microRNA-induced silencing complex (miRISC) protein TNRC6 (also called GW182) uses dispersed tryptophan-containing repeats in unstructured regions to recruit the CCR4–NOT nuclease complex leading to mRNA deadenylation and inhibition of translation initiation according to new research.

One of the most versatile regulators of actin assembly, the WASP homology 2 (WH2) domain, reveals previously unknown facets by combining with a newly discovered actin-nucleating dimeric structure in the effector protein VopL from Vibrio parahaemolyticus.

Mechanistic details about complexin's contradictory double life as both a facilitator and an inhibitor of SNARE-mediated synaptic vesicle fusion have been challenging to uncover. A series of studies in this issue addresses the problem by revealing a switchable complexin conformation in which fusion arrest occurs when complexin clamps neighboring SNAREs.

The RING protein RBX-1 is implicated in both NEDDylation and ubiquitylation reactions. In this issue, new structural analysis reveals how conformational flexibility of the RBX-1 linker allows for a marked reorientation of the CUL1–RBX1 complex to facilitate transfer of NEDD8 or ubiquitin by closing the gap between the E2 catalytic site and the substrate.

The mechanisms of dynein activity have remained a mystery because of dynein's size and complexity, but two papers now shed light on how dynein functions at the molecular level.

A new study reveals that rewiring of MAPK signaling in cells expressing mutant RAS includes ERK-mediated BRAF inactivation and the concomitant activation of CRAF, partly through amplification by the phosphodiesterase 4 isoform.

In this issue, a wide array of structural and biochemical techniques are applied to reveal the molecular details of activity regulation in one of life's most essential enzymes, the ribonucleotide reductase.

Glutamate receptor ion channels use the free energy of ligand binding to trigger ion channel activation and desensitization. In this issue, an analysis of all-atom molecular dynamics simulations dissects the binding process, reveals a substantial gain in free energy produced by domain closure for agonists and reports unique energy landscapes for individual ligands.

Discrimination between self and non-self surfaces by the complement system of innate immunity has long been enigmatic. Finally, two papers provide structural insights into host protection against indiscriminate immune surveillance.

In this issue, two papers present contrasting models for the machinations of the measles virus attachment protein. Here we discuss how these reports illuminate possible intersubunit motions made by the protein as it drives the fusion of viral and cellular membranes during infection and further our understanding of this global scourge.

The interaction of autotaxin with its substrates leads to the production of lysophosphatidic acids (LPA), bioactive lipids with an emerging prominent role in inflammation and cancer. Two papers in this issue tell the previously unknown story of autotaxin, from substrate discrimination to highly efficient local delivery of LPA to target receptors.

How can a single protein recognize and bind a variety of partner proteins that vary in sequence and structure? Analysis of the nuclear export receptor CRM1 provides new insight and surprising conclusions.

The interaction of the Fas death domain (DD) with the adaptor protein FADD is a critical step in assembling the death-inducing signaling complex (DISC). Using structural and biophysical approaches, two recent papers reveal the core stoichiometry to be a 5Fas:5FADD complex.

The N-end rule pathway is a proteolytic system in which recognition components (N-recognins) recognize a set of N-terminal residues as part of degradation signals (N-degrons). Two studies in this issue report the structures of Ubr boxes, a substrate recognition domain of eukaryotic N-recognins. We discuss how eukaryotic and prokaryotic N-recognins use a similar molecular principle to recognize a different set of N-degrons.