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AlphaFold 3 represents a breakthrough in predicting the 3D structures of complexes directly from their sequences, offering insights into biomolecular interactions. Extending predictions to molecular behavior and function requires a shift from viewing biomolecules as static 3D structures to dynamic conformational ensembles.
Microtubules within cells often have 13 protofilaments but are nucleated by multi-protein y-TuRCs complexes that display 14 γ-tubulin molecules. High-resolution cryo-EM structures of γ-TuRCs after nucleation show that these γ-TuRCs ‘close’ during nucleation to display only 13 γ-tubulin molecules for protofilament assembly.
Overexpression of the RNA methyltransferase METTL6 leads to increased proliferation and promotes cancer. Our cryo-electron microscopy (cryo-EM) and biochemical analyses reveal that METTL6 requires seryl-tRNA synthetase as a cofactor to efficiently generate 3-methyl-cytosine in serine tRNAs.
Poxviruses range from deadly smallpox to attenuated vaccinia virus used in vaccines and oncolytic vectors. Despite their broad, if antithetical, effects on humankind, the mechanistic details of poxvirus assembly are not known. Here we discuss advances in revealing the structure of the palisade layer which underlies the viral core morphology.
An iron-induced ferroptosis screen revealed PRDX6 as a selenoprotein-synthesis factor. Loss of PRDX6 substantially decreased expression of the selenoprotein GPX4, a master regulator of ferroptosis, and induced ferroptosis. Mechanistically, PRDX6 increases the efficiency of selenium use by acting as a selenium delivery protein.
Using next-generation cryo-EM and mass spectrometry, we identified 235 chemical modifications in the sub-2 Å resolution structure of the full human 80S ribosome. The newly identified rRNA modifications were found to create new hydrogen bond patterns for riboses and uridines. Ion visualization revealed that Mg2+-associated water molecules are variably substituted by side chains. This study provides the molecular basis for the stabilization of A–U or A–Ψ base pairs and RNA–protein interactions.
Cryo-electron microscopy (cryo-EM) imaging of DNA replication origin activation explains the role of Mcm10, a minichromosome maintenance (MCM) protein homolog, during initiation. Mcm10 acts as a wedge to split the two MCM hexamers of the activated replicative helicase. Diverging replication forks are then established, with changes in the MCM hexamers that promote the topological separation of two DNA strands.
In this Perspective, the authors propose a framework to explain membrane protein biogenesis, wherein different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion.
The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.
The commander complex was recently shown through interactomic screens to be a ubiquitous and conserved protein complex with fundamental biological roles. Two recent reports together revealed the structure of the complete commander assembly and explored its functional implications.
NAD(H) redox homeostasis has a fundamental role in cellular metabolism. We screened for potential modulators of NAD(H) using a genome-scale RNA interference (RNAi) approach combined with SoNar, a high-performance sensor that is sensitive to the redox state of NAD(H). Our analysis identified HES4 as a negative regulator of the NADH/NAD+ ratio that influences pyrimidine biosynthesis and exerts a potent oncogenic effect.
Hexasomes are non-canonical nucleosomes that package DNA with six instead of eight histones. Here, the author contextualizes two recent studies on the interplay of the chromatin remodeler INO80 with hexasomes with historical literature on the subject.
Branch point selection is required for pre-mRNA splicing, and its mis-regulation is associated with many diseases. Two structural studies provide insights into the dynamics of active site formation and the spliceosomal proteins that may contribute to activation of the correct branch point in eukaryotic introns.
Targeted biologics delivery requires programming multicomponent protein nanomaterials to enable selective targeting and response to environment changes in a single unified framework. A novel protein nanoparticle platform has been designed to modulate cell-surface target specificity, cargo packaging, and pH-dependent release of encapsulated cargo, providing exciting possibilities in biologics delivery.
Stabilization of a branch structure would intuitively suggest a direct connection between trunk and bough, but in actin filament networks, cortactin clamps the branching Arp2/3 complex to the daughter filament. This has fundamental consequences for mechanistic understanding of actin branch turnover and cortactin biology.
ADP-ribosylation regulates the activity of numerous proteins involved in the DNA damage response and repair. A new study shows that telomeric DNA can be ADP-ribosylated by PARP1, and prompt removal of the ADP-ribose by TARG1 is essential to preserve telomere integrity, unveiling DNA–ADP-ribosylation as a novel player in telomere stability.
Systemic RNA interference (RNAi) in Caenorhabditis elegans is initiated by SID-1-mediated double-stranded RNA (dsRNA) internalization. By combining cryo-electron microscopy (cryo-EM), in vitro and in vivo assays, we show how SID-1 specifically recognizes dsRNA and provide important insights into dsRNA internalization by SID-1.
The human cytoskeleton consists of three major classes of filaments: microfilaments, microtubules and intermediate filaments. Here, we summarize recent progress in deciphering the structure and function of intermediate filaments and their implications for human disease.
Spliceosome biogenesis and recycling remains a largely unexplored area. Two papers now reveal how protein chaperones remodel the 20S U5 snRNP, leading to formation of the U4/U6.U5 tri-snRNP.