Volume 26 Issue 7, July 2019

New structural work sheds light on the architecture of otopetrin channels, offering insights into the mechanisms for proton permeation in this family.

Abasic sites are among the most frequent DNA lesions, and when they occur within single-stranded DNA, their repair can give rise to genomic instability and mutations. One mechanism for the protection of abasic sites involves covalent attachment of 5-hydroxymethylcytosine-binding, embryonic stem cell–specific (HMCES) protein to DNA. Now, two research groups have elucidated the structural basis of the action of HMCES and its bacterial equivalent, YedK, revealing a unique and intriguing chemistry of DNA–protein crosslink formation.

The ‘tubulin code’, a set of post-translational modifications to the microtubule cytoskeleton that include removal of the C-terminal Tyr of α-tubulin, regulates the biological function of the polymer. Three studies now report structures of VASH1–SVBP and VASH2–SVBP heterodimers and provide insights into how these proteases recognize and cleave the terminal Tyr of α-tubulin.

Bryan Roth reviews how insights into the structures of G protein–coupled receptors that are targets of neuropsychiatric drugs contribute to understanding of their functions as well as to the discovery of new chemical tools and drugs.

Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from the extra-neuronal space. This Review discusses recent advances in elucidating the structural dynamics and allosteric regulation of MATs.

Numerous proteins in dendrites and axons are synthesized locally. In this Review, the authors summarize current evidence for local mRNA translation in neurons and discuss the neuronal functions shown to be served by this process.

Crystal structure of the tubulin carboxypeptidase complex between vasohibin and SVBP, combined with mutagenesis, reveals the residues responsible for substrate recognition and cleavage.

Crystal structures of human vasohibin 1 and 2 in complex with small vasohibin-binding protein (SVBP) in the absence and presence of different inhibitors and a C-terminal α-tubulin peptide define the structural basis of tubulin detyrosination.

Crystal structures of human VASH1–SVBP alone, in complex with a tyrosine-derived covalent inhibitor and bound to parthenolide, explain the requirement for SVBP during tubulin detyrosination and reveal the basis for substrate recognition.

A solid-state NMR structure of an amyloid fibril formed by synthetic human glucagon reveals two distinct β-strand conformations that alternate in an antiparallel fashion along the fibril axis.

Structures of human equilibrative nucleoside transporter 1 in complex with either dilazep or NBMPR reveal distinct inhibitory mechanisms of these drugs, providing insight for rational design of improved therapeutics modulating nucleoside transport.

Crystal structures of the human HMCES SRAP domain in complex with DNA substrates demonstrate how the SRAP domain interacts with a variety of single-strand- and double-strand-containing DNA structures found at DNA-damage sites.

HMCES protects abasic sites that block DNA replication via covalent protein attachment. Crystal structures of the Escherichia coli HMCES homolog YedK reveal that the conserved SRAP domain forms a thiazolidine linkage with the abasic site, explaining the stability of the DNA-protein cross-link and its specificity for DNA lesions at stalled replication forks.

Cryo-EM structures of fibrils formed by two segments from TDP-43 that are essential for aggregation of the full-length protein reveal fibril polymorphism and suggest mechanisms for pathogenesis.

The previously unknown human prenyltransferase, GGTase3, geranylgeranylates the ubiquitin ligase FBXL2, which bears a motif predicted to be recognized by GGTase1. The structure of the GGTase3–FBXL2–SKP1 complex reveals the basis of GGTase3 substrate specificity.

The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.

A CDK multisite phosphorylation code ensures that CDK can signal via hundreds of distinct targets to provide a temporally ordered phosphorylation pattern required for proper execution of the cell cycle.