The fork protection complex promotes parental histone recycling and epigenetic memory

Cell, Год журнала: 2024, Номер 187(18), С. 5029 - 5047.e21

Опубликована: Авг. 1, 2024

The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator symmetric histone inheritance. mutants key connector domain disrupted segregation lagging strand comparable Mcm2 histone-binding mutants. Both showed clonal asymmetric loss H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning by Mcm2, with bridging binding. Biochemical functional analysis validated this model revealed duality function: disabling binding lagging-strand recycling while another mutation impaired leading recycling. We propose toggles between pathways, part intra-replisome co-chaperoning, ensure transmission both daughter cells.

Язык: Английский

---

Diverse anti-defence systems are encoded in the leading region of plasmids

Nature, Год журнала: 2024, Номер 635(8037), С. 186 - 192

Опубликована: Окт. 9, 2024

Plasmids are major drivers of gene mobilization by means horizontal transfer and play a key role in spreading antimicrobial resistance among pathogens

Язык: Английский

---

Combinatorial selective ER-phagy remodels the ER during neurogenesis

Nature Cell Biology, Год журнала: 2024, Номер 26(3), С. 378 - 392

Опубликована: Март 1, 2024

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis calcium ion flux inter-organelle communication. A case in point concerns the process of neurogenesis, where refined tubular ER network is assembled via shaping proteins into newly formed neuronal projections create highly polarized dendrites axons. Previous studies have suggested role for autophagy remodelling, as autophagy-deficient neurons vivo display axonal accumulation within synaptic boutons, membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory autonomic neuropathy. However, our understanding mechanisms underlying selective removal individual receptors limited. Here we combine tractable induced neuron (iNeuron) system monitoring remodelling during vitro differentiation proteomic computational tools quantitative autophagy. Through analysis single combinatorial mutants, delineate extent which each contributes both magnitude selectivity clearance. We define specific subsets membrane or lumenal preferred clients distinct receptors. Using spatial sensors reporters, demonstrate receptor-specific autophagic capture axons, directly visualize membranes autophagosomes by cryo-electron tomography. This molecular inventory versatile genetic toolkit provide framework contributions reshaping cell state transitions.

Язык: Английский

---

Genome modeling and design across all domains of life with Evo 2

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Abstract All of life encodes information with DNA. While tools for sequencing, synthesis, and editing genomic code have transformed biological research, intelligently composing new systems would also require a deep understanding the immense complexity encoded by genomes. We introduce Evo 2, foundation model trained on 9.3 trillion DNA base pairs from highly curated atlas spanning all domains life. train 2 7B 40B parameters to an unprecedented 1 million token context window single-nucleotide resolution. learns sequence alone accurately predict functional impacts genetic variation—from noncoding pathogenic mutations clinically significant BRCA1 variants—without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that autonomously breadth features, including exon–intron boundaries, transcription factor binding sites, protein structural elements, prophage regions. Beyond its predictive capabilities, generates mitochondrial, prokaryotic, eukaryotic sequences at genome scale greater naturalness coherence than previous methods. Guiding via inference-time search enables controllable generation epigenomic structure, which demonstrate first scaling results in biology. make fully open, parameters, training code, inference OpenGenome2 dataset, accelerate exploration design complexity.

Язык: Английский

---

FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains

Nature Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Abstract O -Fucosylation plays crucial roles in various essential biological events. Alongside the well-established -fucosylation of epidermal growth factor-like repeats by protein -fucosyltransferase 1 (POFUT1) and thrombospondin type POFUT2, we recently identified a on elastin microfibril interface (EMI) domain Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis CRISPR–Cas9 knockouts, demonstrate that FUT10 FUT11, originally annotated UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, renamed them POFUT3 POFUT4, respectively. Like POFUT1/2, POFUT3/4 function endoplasmic reticulum, require folded structures modification participate non-canonical reticulum quality control pathway domain-containing secretion. This finding expands repertoire provides an entry point further exploration this emerging field -fucosylation.

Язык: Английский

---

Fascin structural plasticity mediates flexible actin bundle construction

Nature Structural & Molecular Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 20, 2025

Abstract Fascin cross-links actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. dysregulation drives aberrant cell migration during metastasis, fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-EM, cryo-electron tomography coupled with custom denoising computational modeling to probe human fascin-1’s F-actin cross-linking mechanisms across spatial scales. Our cross-bridge structure reveals an asymmetric binding conformation is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis simulations show how structural plasticity enables bridge varied interfilament orientations, accommodating mismatches between F-actin’s helical symmetry packing. Tomography many-filament uncover geometric rules underlying emergent patterns, well accumulation unfavorable limit size. Collectively, this work shows harnesses fine-tuned nanoscale dynamics build regulate micron-scale bundles.

Язык: Английский

---

Conformational dynamics of a multienzyme complex in anaerobic carbon fixation

Science, Год журнала: 2025, Номер 387(6733), С. 498 - 504

Опубликована: Янв. 30, 2025

In the ancient microbial Wood-Ljungdahl pathway, carbon dioxide (CO 2 ) is fixed in a multistep process that ends with acetyl–coenzyme A (acetyl-CoA) synthesis at bifunctional monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). this work, we present structural snapshots of CODH/ACS from gas-converting acetogen Clostridium autoethanogenum , characterizing molecular choreography overall reaction, including electron transfer to CODH for CO reduction, methyl corrinoid iron-sulfur protein (CoFeSP) partner ACS active site, and acetyl-CoA production. Unlike CODH, multidomain undergoes large conformational changes form an internal connection accommodate CoFeSP transfer, protect reaction intermediates. Altogether, structures allow us draw detailed mechanism enzyme, which crucial fixation anaerobic organisms.

Язык: Английский

---

Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Protein-protein interactions (PPIs) are ubiquitous in biology, yet a comprehensive structural characterization of the PPIs underlying cellular processes is lacking. AlphaFold-Multimer (AF-M) has potential to fill this knowledge gap, but standard AF-M confidence metrics do not reliably separate relevant from an abundance false positive predictions. To address limitation, we used machine learning on curated datasets train structure prediction and omics-informed classifier (SPOC) that effectively separates true predictions PPIs, including proteome-wide screens. We applied SPOC all-by-all matrix nearly 300 human genome maintenance proteins, generating ∼40,000 can be viewed at predictomes.org, where users also score their own with SPOC. High-confidence discovered using our approach enable hypothesis generation maintenance. Our results provide framework for interpreting large-scale screens help lay foundation interactome.

Язык: Английский

---

Structure of human PINK1 at a mitochondrial TOM-VDAC array

Science, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson’s Disease, but how is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human an endogenous array TOM and VDAC complexes. Symmetric arrangement two core around central VDAC2 dimer facilitated by TOM5 TOM20, both which also bind C-lobes. enters mitochondria through proximal TOM40 barrel complex, guided TOM7 TOM22. Our explains complex regulated oxidation, uncovers previously unknown TOM-VDAC assembly, reveals physiological substrate traverses during translocation.

Язык: Английский

---

Evolutionary origins of archaeal and eukaryotic RNA-guided RNA modification in bacterial IS110 transposons

Nature Microbiology, Год журнала: 2025, Номер 10(1), С. 20 - 27

Опубликована: Янв. 2, 2025

Язык: Английский

---