p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners.

The p53 transcription factor family consists of the three members p53, p63, and p73. Both p63 and p73 exist in different isoforms that are well characterized. Isoforms have also been identified for p53 and it has been proposed that they are responsible for increased cancer metastasis.

Martini 3 Coarse-Grained Models for Carbon Nanomaterials.

The Martini model is a coarse-grained force field allowing simulations of biomolecular systems as well as a range of materials including different types of nanomaterials of technological interest. Recently, a new version of the force field (version 3) has been released that includes new parameters for lipids, proteins, carbohydrates, and a number of small molecules, but not yet carbon nanomaterials. Here, we present new Martini models for three major types of carbon nanomaterials: fullerene, carbon nanotubes, and graphene.

Bacterial cell widening alters periplasmic size and activates envelope stress responses.

The Rcs signal transduction system is a phosphorelay responsible for sensing enterobacterial cell envelope stresses. In Escherichia coli, the Rcs system is required to survive treatment with A22 and mecillinam, antibiotics that perturb cell size. To test whether size changes are correlated with envelope damage and thereby sensed by the Rcs system, we tuned E.

A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles.

Eukaryotic cells use a multi-layered immune response to combat intracellular pathogens. The ubiquitin ligase ZNFX1 has emerged as a crucial yet little understood player that regulates the immune response while protecting against RNA viruses. Our study unveils the molecular mechanism of ZNFX1, mediated by the joint activity of a helicase serving as a nucleic acid sensor and a non-conventional E3 module featuring a split active site.

STIM1 transmembrane helix dimerization captured by AI-guided transition path sampling.

Stromal interaction molecule 1 (STIM1) is a Ca-sensing protein in the endoplasmic reticulum (ER) membrane. The depletion of ER Ca stores induces a large conformational transition of the cytosolic STIM1 C-terminus, initiated by the dimerization of the transmembrane (TM) domain. We use the AI-guided transition path sampling algorithm aimmd to extensively sample the dimerization of STIM1-TM helices in an ER-mimicking lipid bilayer.

Conserved function of the HAUS6 calponin homology domain in anchoring augmin for microtubule branching.

Branching microtubule nucleation is a key mechanism for mitotic and meiotic spindle assembly and requires the hetero-octameric augmin complex. Augmin recruits the major microtubule nucleator, the γ-tubulin ring complex, to pre-existing microtubules to direct the formation of new microtubules in a defined orientation. Although recent structural work has provided key insights into the structural organization of augmin, molecular details of its interaction with microtubules remain elusive.

YTHDF proteins and mA-RNA clients undergo autophagic turnover during contact inhibition.

The YTHDF protein family plays a critical role in cancer development by recognizing and regulating the stability of N6-methyladenosine (mA)-modified RNA. Here, we reveal an autophagy-dependent mechanism controlling YTHDF protein levels. Using contact inhibition as a cellular model system, we show YTHDF proteins to be rapidly degraded, coinciding with increased autophagy and decreased mTOR activity.

Opportunities in proximity modulation: Bridging academia and industry.

In the past decade, exciting therapeutic strategies to harness the ubiquitin-proteasome system (UPS) for degradation of target proteins have emerged. Proximity-inducing modalities are at the center of these strategies and act by modulating protein-protein interactions. While we are still learning to harvest this approach, it holds tremendous promise for developing treatments for hitherto undruggable proteins.

Subtomogram averages of mitochondrial ATP synthase dimers from plants show a conserved extra density at the peripheral stalk.

We analyzed ATP synthase dimers in mitochondria purified from four plant species by subtomogram averaging, using Saccharomyces cerevisiae as a control. The purified mitochondria were plunge-frozen and broken mitochondria were examined by electron cryo-tomography. In each case, the ATP synthase dimers formed extensive rows along the tightly curved cristae ridges.

The small GTPase Ran defines nuclear pore complex asymmetry.

Nuclear pore complexes (NPCs) bridge across the nuclear envelope and mediate nucleocytoplasmic exchange. They consist of hundreds of nucleoporin building blocks and exemplify the structural complexity of macromolecular assemblies. To ensure transport directionality, different nucleoporin complexes are attached to the cytoplasmic and nuclear face of the NPC.

Detection and quantitation of small proteins using mass spectrometry.

Small proteins or microproteins, despite long being ignored, have important roles in the regulation of larger protein complexes, metabolic pathways and gene expression. However, these proteins remain underrepresented in proteomics studies due to low detection efficiency in traditional mass spectrometry workflows. Their inherent characteristics often lead to depletion during sample preparation and a low detection efficiency in liquid chromatography-mass spectrometry (LC-MS).

In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.

Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in and . Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals.

Automated removal of corrupted tilts in cryo-electron tomography.

Cryo-electron tomography (cryo-ET) enables the visualization of macromolecular structures in their near-native cellular environment. However, acquired tilt series are often compromised by image corruption due to drift, contamination, and ice reflections. Manually identifying and removing corrupted tilts is subjective and time-consuming, making an automated approach necessary.

Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.

Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex.

The rapidly expanding role of LC3-interacting regions in autophagy.

LC3-interacting regions (LIRs), or Atg8-interacting motifs (AIMs), are short linear motifs found in unstructured loops or intrinsically disordered regions of many autophagy-related proteins. LIRs were initially identified for their role in binding to Atg8 family proteins on autophagosomal membranes. However, emerging evidence suggests that LIRs and their surrounding residues mediate interactions with a wide array of proteins beyond Atg8s.

Structures of TOM complexes with bound preproteins.

Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complexes from the thermophilic fungus , obtained by single-particle electron cryomicroscopy.

Electron flow in hydrogenotrophic methanogens under nickel limitation.

Methanogenic archaea are the main producers of the potent greenhouse gas methane. In the methanogenic pathway from CO and H studied under laboratory conditions, low-potential electrons for CO reduction are generated by a flavin-based electron-bifurcation reaction catalysed by heterodisulfide reductase (Hdr) complexed with the associated [NiFe]-hydrogenase (Mvh). F-reducing [NiFe]-hydrogenase (Frh) provides electrons to the methanogenic pathway through the electron carrier F (ref.

A constricted mitochondrial morphology formed during respiration.

Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear.

The Multifaceted Role of Calcium Signaling in Regulated Necrosis.

Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, and ferroptosis, and resembles the calcium surge triggered by pore-forming toxins. The complexity of calcium signaling is orchestrated by specialized channels in various cellular compartments and calcium-binding proteins that respond to localized calcium concentrations.

P-type ATPase magnesium transporter MgtA acts as a dimer.

Magnesium (Mg) uptake systems are present in all domains of life, consistent with the vital role of this ion. P-type ATPase Mg importers are required for bacterial growth when Mg is limiting or during pathogenesis. However, insights into their mechanisms of action are missing.

The RNF/NQR redox pumps: a versatile system for energy transduction in bacteria and archaea.

The Na (or H)-translocating ferredoxin:NAD oxidoreductase (also called RNF, rhodobacter nitrogen fixation, complex) catalyzes the oxidation of reduced ferredoxin with NAD, hereby generating an electrochemical gradient. In the reverse reaction driven by an electrochemical gradient, RNF provides reduced ferredoxin using NADH as electron donor. RNF plays a crucial role in the metabolism of many anaerobes, such as amino acid fermenters, acetogens, or aceticlastic methanogens.

Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.

VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear.

Phosphoribosyl ubiquitination of SNARE proteins regulates autophagy during Legionella infection.

Legionella pneumophila is an intracellular pathogen that causes Legionnaires' disease. The bacteria release effector proteins, some of which remodel host autophagic-lysosomal pathways. One such effector is RavZ, which delipidates ATG8 proteins, making compromising autophagy in Legionella-infected cells.

Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases.

A wide range of human diseases are associated with protein misfolding and amyloid aggregates. Recent studies suggest that in certain neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and various tauopathies, protein aggregation may be promoted by virus-like particles (VLPs) formed by endogenous retroviruses (ERVs). The molecular mechanisms by which these VLPs contribute to protein aggregation, however, remain enigmatic.

Dipolar Cross-Correlations in Aqueous Systems: How Surfaces Influence Water's Action at a Distance.

Water exhibits several anomalous properties that shape the way water functions in biological and chemical environments. For example, the unusually large dielectric constant of water can be traced back to dipolar cross-correlations, which are manifestations of both its dipole moment and the extended hydrogen bond (HB) network. However, a common platform that explores the origins of such cross-correlations and their influence on the properties of water is missing.