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Although histone H3 Lys4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription is lacking. New studies with the histone methyltransferase MLL2 in a cell-free transcription system now establish a direct causal role for MLL2-mediated H3K4 methylation in transcription and identify AKAP95 as a new modulator of H3K4 methylation.
How the activity of transposable elements is regulated is not well understood. A new study now shows that the Microprocessor complex, which is required for microRNA biogenesis, also recognizes and binds RNAs derived from human LINE-1, Alu and SVA retrotransposons and that it acts as a post-transcriptional repressor of mammalian retrotransposons in vivo.
Ligand-gated ion channels are susceptible to inactivation upon prolonged exposure to their ligand, a process known as desensitization. A sodium-binding pocket within the KAR-type glutamate receptor GluK2 is now shown to have a crucial role in this process, as desensitization is shown to occur only when the ligand is bound without cation pocket occupancy.
The deubiquitinating enzyme OTUB1 binds charged E2 intermediates and prevents ubiquitin transfer. OTUB1 can also bind uncharged E2, and this interaction is now shown to stimulate OTUB1's deubiquitination activity. Thus, OTUB1–E2 complexes might regulate levels of ubiquitin conjugation in response to available free ubiquitin and the ratio of charged to uncharged E2.
Embryonic stem cells (ESCs) possess a unique chromatin landscape in which 'bivalent' domains of trimethylated histone H3 Lys4 (H3K4me3) and Lys27 (H3K27me3) mark key lineage-specific genes. A new study now reports the identification of Mll2 (KMT2b) as the enzyme responsible for implementing H3K4me3 on bivalently marked promoters in ESCs.
The crystal structure of the full catalytic core of p300 reveals the presence an unexpected RING domain, within the CH2 region, that folds over the HAT-domain substrate-binding pocket. Mutations that destabilize the RING-HAT interaction and increase acetyltransferase activity in vitro are also found in B-cell lymphomas, thus suggesting an important function for this autoinhibitory interaction in vivo.
How plant pri-miRNAs with complex secondary structures are recognized and processed has been unclear. A new study now suggests that unlike canonical processing of pri-miRNAs, terminal loop–branched pri-miRNAs can be processed by Dicer-like 1 (DCL1) complexes bidirectionally, either from the lower stem to the terminal loop or vice versa, resulting in productive and abortive processing of miRNAs, respectively.
Proteins containing repeats of the WASP homology 2 (WH2) actin-binding module are multifunctional regulators of actin nucleation and assembly. Now biochemical analyses of VopF from Vibrio cholerae reveal a new regulatory mechanism of actin-filament barbed-end dynamics including enhanced nucleation, uncapping and assisted elongation.
Elongation factor G (EF-G) facilitates the movement of tRNA and mRNA by one codon, which is coupled to the ratchet-like rotation of the ribosome complex and is triggered by EF-G–mediated GTP hydrolysis. The crystal structure of pretranslocational ribosome bound to EF-G trapped with a GTP analog provides insight into how the ribosome and EF-G are coordinated to modulate the GTPase activity.
N-terminal acetylases catalyze the cotranslational modification of myriad proteins. Structural and mutational analyses of the NatA complex, comprising a catalytic and auxiliary subunit, and of the catalytic subunit alone reveal the molecular basis for substrate binding, specificity and mode of catalysis, and the role of the auxiliary subunit in these activities.
The activity of PLK1, a key mitotic regulator, is tightly regulated during the cell cycle through both phosphorylation and protein-protein interactions. The crystal structure of PLK1's kinase domain bound to the polo-box domain now provides a structural framework for the regulation of PLK1 through autoinhibition.
Calmodulin (CaM) regulates a variety of membrane channels in response to Ca2+, but the precise mechanisms are still unclear. Now a combination of single-particle EM, molecular dynamics simulations and functional assays is used to elucidate the structure of Ca2+–CaM bound to the full-length aquaporin AQP0, revealing a cytoplasmic gate that is closed upon CaM binding to control channel permeability in an allosteric manner.
The Arp2/3 complex regulates the actin cytoskeleton by nucleating branched actin filaments in response to cellular signals and is in turn controlled by regulators including GMF. The crystal structure of GMF bound to Arp2/3 provides insight into how GMF inhibits actin nucleation and dissembles branches.
HP1 proteins bind methylated histone H3 Lys9, a hallmark of heterochromatin, and mediate heterochromatin spreading by recruiting histone methyltransferase activities. New studies have now identified a long noncoding RNA called BORDERLINE that prevents spreading of the HP1 protein Swi6 and histone H3 Lys9 methylation beyond the pericentromeric repeat region of fission yeast chromosome 1.
Combined with kinetic analyses, the high resolution structure of kinesin-1 bound to a tubulin dimer offers a much-anticipated view of the motor-microtubule interface that illuminates the key step of neck-linker docking and of the structural basis for microtubule-accelerated ATP hydrolysis and motility.
In dimeric RING E3 ligases, the tail domain of the second subunit primes the transfer reaction. The crystal structure of human Tyr363-phosphorylated CBL-B in complex with ubiquitin-linked E2 UbcH5Band a peptide substrate now shows that a phosphorylated residue can act as the priming element in monomeric RING E3s.
In immune cells, CRAC channels in the plasma membrane regulate store-operated Ca2+ entry in response to STIM1, a sensor protein located in the endoplasmic reticulum (ER) membrane. New biophysical assays show how dimerization of STIM1's ER-luminal domains causes extension of its cytoplasmic domains toward the plasma membrane to contact the ORAI pore and activate the channel, revealing the structural dynamics of this Ca2+-signaling mechanism.
Eukaryotic DNA replication begins with recruitment of the ring helicase MCM2-7 by the origin recognition complex (ORC) in a reaction facilitated by initiation factors Cdc6 and Cdt1. A new cryo-EM structure of a helicase loading intermediate, the ORC–Cdc6–Cdt1–MCM2-7 complex, unexpectedly reveals both MCM2-7 and ORC hexamers encircling the DNA, and shows the arrangement of all 14 subunits within the helicase-loader complex.
Most mammalian promoters are inherently bidirectional, but transcription only elongates productively in one direction. Data presented in this paper demonstrate that at least part of the answer lies in the asymmetric distribution of polyadenylation-site sequences around human gene promoters causing termination of upstream antisense transcription.
The general transcription factor TFIID comprises TATA-binding protein (TBP) and TBP-associated factors (TAFs). The high-resolution structure of yeast TBP in complex with yeast TAF1 containing both transcriptionally activating and repressing regions reveals detailed and specific molecular patterns of interactions with TBP and their significance for transcriptional regulation.
