News & Views in 2016

All current evidence indicates a central role for α-synuclein (α-SYN) amyloid fibrils in Parkinson's disease and other synucleinopathies, but the precise relationship between amyloid aggregates and the resulting phenotype remains poorly understood, partly because of the lack of reliable three-dimensional structures. In this issue, the structure of a toxic α-SYN fibril is now presented at unprecedented resolution.

Translation elongation entails a one-codon movement of the mRNA–tRNA complex along the mRNA and is catalyzed by the forward translocase EF-G. The structurally related back-translocase EF4 catalyzes movement in the opposite direction when the ribosome stalls, but its physiological role in mammals had been unknown. Genetic ablation of EF4 in mice is now found to cause testis-specific mitochondrial deficiency and impaired spermatogenesis.

Brown fat has a tremendous capacity to oxidize fatty acids and generate heat, owing to the presence of an 'uncoupling protein', UCP1. The fatty acids themselves are understood to activate UCP1, but Chouchani et al. now propose that oxidation of a critical cysteine residue on UCP1 is additionally required to sensitize the protein to fatty acids.

The fundamental mechanics of how EF-G catalyzes translocation of the mRNA and tRNA pairs on the ribosome has been intensely studied for over three decades. Two kinetic studies now reveal the sequence of events and the timing of key conformational changes in the ribosome during translocation and identify new intermediates in this complex process.

Two new studies of the CRISPR nuclease Cpf1 reveal the structural and catalytic flexibility of this leaner, meaner alternative to Cas9.

Structures of the human orexin receptor 1 (hOX₁R) bound to a selective drug and the dual (hOX₁R- and hOX₂R-targeting) antagonist suvorexant reveal molecular mechanisms of selectivity in orexin-receptor subtypes.

Three recent reports explore how PRDM9 binds to meiotic hotspots within the genome and provide compelling evidence that hotspot erosion leads to speciation.

During assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), the RNA-binding protein (RBP) Gemin5 recognizes the snRNP code and interacts with the large Gemin2–SMN complex. So et al. now find that Gemin2 also interacts with U1-70K, thereby conferring a preferential advantage on U1 snRNP assembly, and they extrapolate that SMN–Gemin2 serves a general ribonucleoprotein-exchange function.

50 years ago, Jardetzky proposed the alternating-access model, which has shaped the theoretical understanding of how substrates are carried across cell membranes. Two studies now demonstrate that transporters from distinct families undergo unexpectedly large elevator-like movements and also suggest that an 'elevate and twist' mechanism is a common means of achieving alternating access across the membrane.

Unraveling the molecular arms race between virus and host has been taken to a new level. A cryo-EM study reveals in unprecedented detail how the herpesvirus immune-evasion protein ICP47 inhibits the peptide transporter TAP.

Two structural studies provide new insights into the mechanisms regulating the DNA binding and activation of human HSF family members.

Release of neurotransmitters occurs by opening of a fusion pore in a manner thought to be mediated by SNARE proteins, but whether the fusion pore is a lipidic or a proteinaceous structure is controversial. A new study using very small nanodiscs shows that it is both.

Rea1 is an ATPase related to dynein motor proteins that has been implicated in the biogenesis of the 60S ribosomal subunit. A new cryo-EM study vividly demonstrates the power of structural methods, deciphering the role of Rea1 in monitoring key pre-60S maturation steps before the acquisition of export competence in budding yeast.