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The eukaryotic 26S proteasome is responsible for degrading virtually any protein with an appropriate ubiquitin signal, and in the process ubiquitin is spared and recycled. Two studies of the proteasome-associated deubiquitinase UBP6 now shed light on how deubiquitination coordinates the cycle of substrate processing.
New methods permit genomic mapping of oxidized methylcytosines at single-base resolution and suggest new regulatory functions for 5-methylcytocine (5mC) derivatives 5hmC, 5fC and 5caC in the mammalian genome.
MCM2, a component of the replicative helicase, can bind histones H3–H4 in both tetrameric and dimeric form, depending on the presence of the histone chaperone ASF1. A structural analysis of the complexes now sheds light on key domains in the MCM2 protein that prove important for cell proliferation.
Two new studies reveal mechanistic insights into how neurons control the assembly of SNARE complexes and the rapid fusion of synaptic vesicles. Structural, biophysical and functional experiments are combined to elucidate the roles of two critical regulators: Munc13 and synaptotagmin.
Ten years ago, the repulsive guidance molecules (RGMs), a family of three glycosylphosphatidylinositol–anchored glycoproteins, were identified as highly specific co-receptors of the bone morphogenetic proteins (BMPs). Newly reported crystal structures provide exciting insights into how RGM co-receptors may modulate BMP signaling.
How do molecular interactions determine the period length of a circadian oscillator? In mammals, a disordered region of the BMAL1 transcription factor that is able to interact with activators or repressors seems to perform this function.
Sex-determining transcription factors recognize their genomic target sites through mechanisms of DNA base-and-shape readout in combination with cooperative binding. Murphy et al. reveal that for one such transcription factor, DMRT1, the DNA sequence-and-shape features of its binding sites determine whether it binds DNA as a dimer, trimer or tetramer; they also characterize protein-DNA contacts that affect gender phenotypes in flies and humans.
The identification of a second regulatory checkpoint controlling RNA polymerase II elongation near the poly(A) site of protein-coding genes reveals an additional level of complexity in the modulation of eukaryotic transcriptional elongation and termination.
Dynactin is an essential cofactor for the microtubule-based motor cytoplasmic dynein. Two recent papers report structures obtained by cryo-EM of dynactin, the dynein–dynactin complex and dynein–dynactin bound to its track, the microtubule.
Regulation of integrin activity is critical for human health, and the steps mediating integrin activation are well established. In contrast, the counteracting mechanisms of inactivation are less understood. An integrin inhibitor, filamin, is shown to stabilize the integrin resting state by bondage of the cytoplasmic domains of the integrin heterodimer, thus providing evidence of a new mechanism for integrin retention in the inactive state.
The first structures of a light-driven sodium pump provide insight into the mechanism of ion transport and selectivity. Genetic manipulation of rat neuronal cells and of Caenorhabditis elegans worms demonstrates the utility of such pumps for optogenetic applications.
R-type pyocins, produced by Pseudomonas aeruginosa, are sheath-tube nanomachines that puncture the envelopes of target cells, inducing their death. Cryo-EM studies reveal the atomic structures of the pyocin R2 in its extended precontraction and postcontraction forms, which suggest a mechanism for the contraction process of this molecular syringe.
Mammalian cells have both cytoplasmic and mitochondrial ribosomes, which have long been considered to operate completely independently. However, a new report shows that after heat shock, MRPL18, a human mitochondrial ribosomal protein, binds to cytoplasmic ribosomes to influence translation of heat-shock mRNAs.
Circadian regulation of epigenetic chromatin marks drives daily transcriptional oscillation of thousands of genes and is intimately linked to cellular metabolism and bioenergetics. New work links circadian fluctuations in the activity of the SIRT1 deacetylase, a sensor of the cellular energy state, to histone-methylation changes and the circadian expression of clock-controlled genes.
Although the two B-family human DNA polymerases, pol δ and pol ε, are responsible for the bulk of nuclear genome replication, at least 14 additional polymerases have roles in nuclear DNA repair and replication. In this issue, newly reported crystal structures of two specialized A-family polymerases, pol ν and pol θ, expose these enzymes' strategies for handling aberrant DNA ends.
Transcriptional termination is an important yet incompletely understood aspect of gene expression. Proudfoot, Jopling and colleagues now identify a new Microprocessor-mediated mechanism of transcriptional termination, which acts specifically on long noncoding transcripts that serve as microRNA precursors.
Pioneering studies in voltage-gated potassium channels have described movement of the voltage-sensing domain (VSD) S4 helix across the membrane electric field in molecular detail, but much less is known regarding opening of the intrinsic proton pore within VSDs of voltage-dependent proton channels. By systematically probing local kinematics, a new study reveals that movements in helix S1 correlate with pore opening and are distinct from voltage-sensing movements of the charged S4 segment.
During infection, pathogenic Yersinia species secrete the antiphagocytic factor YopO (or YpkA), which contains a kinase domain and a Rho GTPase guanine nucleotide–dissociation inhibitor (GDI) domain. The structure of YopO in complex with actin, along with biochemical analyses, reveals the mechanism by which YopO uses actin to activate its kinase domain and recruit, phosphorylate and deactivate actin-assembly factors implicated in phagocytic clearance of the bacterium.
Amyloids escape elimination by the proteasome, and their accumulation and subsequent aggregation contribute to various neurodegenerative conditions. A signature feature of amyloidogenic proteins is extended sequences rich in single amino acids. In this issue, Matouschek and colleagues now show that, to initiate degradation, the proteasome prefers substrates that have disordered regions with complex amino acid composition, thus indicating why it fails to rid the cell of most amyloids.
