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Structural basis of the regulation by CDK11 kinase of early spliceosome activation and evidence for its proofreading by DHX15 helicase
Abstract Formation of the activated human spliceosome (B act ) involves major structural rearrangements, leading to the catalytically active U2/U6 RNA core. This process involves at least two intermediates, pre-B act-1 and pre-B act-2 , and is regulated by CDK11-mediated phosphorylation of the U2 snRNP protein SF3B1. However, the mechanisms of this essential step are poorly understood. Here we present the cryo-EM structure of a spliceosome stalled – by the CDK11 inhibitor OTS964 – in a previously undescribed early-activated state, termed pre-B act-OTS , shortly after dissociation of U4 snRNP. In pre-B act-OTS , the U2-SF3B6 protein is retained in a C-terminal region of the super-helical U2-SF3B1 HEAT domain (SF3B1 HEAT ) that clamps the U2/branch-site helix. In contrast, in pre-B act-1 , SF3B6 is repositioned to SF3B1’s N-terminal HEAT repeats, thereby preventing a steric clash of SF3B6 with PRP8 during the pre-B act-OTS -to-pre-B act-1 transition. We infer that the CDK11-mediated phosphorylation of SF3B1 drives the relocation of SF3B6, gating progression to B act formation. In pre-B act-OTS , we also located the RNA helicase DHX15 at the N-terminal region of SF3B1 HEAT , assisted by the SR140/SPF45/CHERP/SUGP1 protein complex. These results suggest the involvement of DHX15 in kinase-mediated proofreading of the early-activated spliceosome, by competing with CDK11’s phosphorylation of SF3B1, and thus with relocation of SF3B6 at SF3B1 HEAT .
Water exchange process and bulk composition regulate slab dynamics and deep earthquakes
Zeolitic isolated protonic acid sites-mediated NH3 storage for robust NOx removal
Robust SWCNT-OH/GO membranes for scalable recovery of moxifloxacin from high-salinity organic wastewater
Architecture of the Wza-Wzc complex that mediates colanic acid translocation across the cell envelope in Gram-negative bacteria
Seconds-scale exfoliation of high-quality 2D crystals enabled by polycyclic aromatic hydrocarbon radical anion-mediated organoalkali intercalation
Bipolar membranes reveal surface-hydroxyl-structure-dependent water dissociation mechanism
Thermoresponsive and xenon-triggered gate-opening in flexible three-dimensional covalent organic framework for selective xenon capture
Mitigating polymer-induced self-inhibition with microenvironment-decoupled Sn(II) single-atom catalysts for pollutant polymerization
A fully solution-processed organic microcavity laser in the strong light-matter coupling regime
Abstract Solid-state semiconductor lasers underpin technologies from telecommunications and data storage to sensing, medical diagnostics, and emerging quantum communication. Polaritons, hybrid exciton-photon states, have further extended this reach by enabling room-temperature effects such as low-threshold lasing and strong optical nonlinearities. Organic semiconductors are attractive for polaritonics because of their large exciton binding energies, strong nonlinearities, and compatibility with solution processing. However, while solution-processed organic films have been widely explored, the optical cavities used for organic polariton lasing have typically relied on vacuum deposition, limiting truly scalable, low-cost, and accessible device fabrication. Here, we show that all-dielectric organic microcavities fabricated entirely by solution processing, including both the mirrors and active layer, operate in the strong coupling regime, exhibit polariton lasing, and support reversible, detuning-dependent redistribution of the condensate at high excitation densities, establishing an accessible and tunable platform for nonlinear organic polariton physics.
High-sensitive glycomics using seGRAP-mass spectrometry uncovers a conserved N-glycome in single human oocytes
Observation of non-adiabatic non-Abelian braiding of matter waves
Unlocking stable intermediate states in SrFeO3-δ through voltage control of oxygen non-stoichiometry
Molecular architecture of heterochromatin at the nuclear periphery of primary human cells
Abstract In eukaryotes, meters of DNA are packaged into micrometer scale nuclei. Nucleosomes, as the major organizational unit, have been extensively studied in vitro, yet the elaborate 3D structure of chromatin inside cells and its distinct oligo-nucleosome arrangements remain poorly resolved. Here, we combine cryo-electron tomography with template matching, subtomogram averaging and molecular simulations to visualize nucleosomes and chromatin structure inside human cells. We confidently assign individual nucleosomes and report their in-situ structure at secondary structure resolution. By predicting the paths of linker DNA, we identify oligo-nucleosome arrangements and uncover higher-order chromatin structures in situ, including a 37-nm wide, elongated but non-fibrous arrangement. In situ structural biology thus reveals the molecular chromatin organization inside cells and sets the stage for 3D genomics.
Viral modulation of sulfur-oxidizing bacteria drives organic carbon sink formation during primary succession in deglaciating ecosystems
Structural and mechanistic insights into primer synthesis initiation by DNA primase
Abstract DNA primases synthesize short primers required for genome replication, yet the mechanism of initial dinucleotide formation remains poorly understood. Here, we investigate the primase encoded by the pRN1 plasmid from the thermoacidophile archaeon Sulfolobus islandicus , a minimal model for primer synthesis. Using nucleotide analogues to slow the reaction, we capture transient intermediates of dinucleotide formation. Structural NMR and modeling reveal that the ancillary domain simultaneously binds the DNA template and two initiating nucleotides. Unexpectedly, only the second nucleotide base-pairs with the template, whereas the first remains unpaired, inducing template-base flipping and linker interaction. This interaction promotes a closed conformation in which the second nucleotide moves from the initiation to the elongation site and the first forms a base pair in the initiation site, positioning both nucleotides for catalysis. These findings reveal a mechanism for template recognition, nucleotide assembly, and proofreading during primer initiation that is likely conserved among primases.
PfApiAT2 is a proline transporter essential for the transmission of Plasmodium falciparum by the mosquito vector
Abstract Plasmodium falciparum oocysts undergo an explosive biomass increase during development in Anopheles mosquitoes, a dramatic growth process likely promoted by as-yet unknown nutrients scavenged from the mosquito. We previously observed in blood-stage parasites, that the amino acid transporter PfApiAT2, although dispensable, regulates proline homeostasis and mediates resistance to halofuginone, a potent proline-tRNA synthetase inhibitor. Here, we demonstrate that PfApiAT2 is a proline-specific transporter essential for early oocyst development in Anopheles gambiae . Halofuginone-resistant pfapiat2 -mutant parasites form stunted oocysts severely defective in sporozoite production. This phenotype is recapitulated in PfApiAT2-knockout parasites that undergo a complete block in sporogony, forming oocysts that stall and degenerate. Remarkably, this growth defect can be rescued by nutrient supplementation to the mosquito vector. By identifying an amino acid transporter essential for oocyst growth, our data unveil a vulnerability in P. falciparum transmission, revealing a critical nutritional dependency of the parasite on its mosquito vector.