Proteomic Profile Regulated by the Immunomodulatory Jusvinza Drug in Neutrophils Isolated from Rheumatoid Arthritis Patients.

Jusvinza is an immunomodulatory drug composed of an altered peptide ligand (APL) designed from a novel CD4+ T cell epitope of human heat shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of rheumatoid arthritis (RA). The peptide induces regulatory T cells and decreases levels of TNF-α and IL-17; pre-clinical and phase I clinical studies support its use for the treatment of RA. This peptide was repositioned for the treatment of COVID-19 patients with signs of hyperinflammation.

In situ architecture of a nucleoid-associated biomolecular co-condensate that regulates bacterial cell division.

In most bacteria, cell division depends on the tubulin-homolog FtsZ that polymerizes in a GTP-dependent manner to form the cytokinetic Z-ring at the future division site. Subsequently, the Z-ring recruits, directly or indirectly, all other proteins of the divisome complex that executes cytokinesis. A critical step in this process is the precise positioning of the Z-ring at the future division site.

Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis.

B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not.

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.

Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγ) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations.

Determination of absolute intramolecular distances in proteins using anomalous X-ray scattering interferometry.

Biomolecular structures are typically determined using frozen or crystalline samples. Measurement of intramolecular distances in solution can provide additional insights into conformational heterogeneity and dynamics of biological macromolecules and their complexes. The established molecular ruler techniques used for this (NMR, FRET, and EPR) are, however, limited in their dynamic range and require model assumptions to determine absolute distance or distance distributions.

Beyond Dimerization: Harnessing Tetrameric Coiled-Coils for Nanostructure Assembly.

Versatile DNA and polypeptide-based structures have been designed based on complementary modules. However, polypeptides can also form higher oligomeric states. We investigated the introduction of tetrameric modules as a substitute for coiled-coil dimerization units used in previous modular nanostructures.

π-HuB: the proteomic navigator of the human body.

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies.

Redesigning error control in cross-linking mass spectrometry enables more robust and sensitive protein-protein interaction studies.

Cross-linking mass spectrometry (XL-MS) allows characterizing protein-protein interactions (PPIs) in native biological systems by capturing cross-links between different proteins (inter-links). However, inter-link identification remains challenging, requiring dedicated data filtering schemes and thorough error control. Here, we benchmark existing data filtering schemes combined with error rate estimation strategies utilizing concatenated target-decoy protein sequence databases.

A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.

The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E (PGE) as a major immune regulatory mechanism of heGDH.

Cryo-electron tomography: en route to the molecular anatomy of organisms and tissues.

Cryo-electron tomography (cryo-ET) has become a key technique for obtaining structures of macromolecular complexes in their native environment, assessing their local organization and describing the molecular sociology of the cell. While microorganisms and adherent mammalian cells are common targets for tomography studies, appropriate sample preparation and data acquisition strategies for larger cellular assemblies such as tissues, organoids or small model organisms have only recently become sufficiently practical to allow for in-depth structural characterization of such samples in situ. These advances include tailored lift-out approaches using focused ion beam (FIB) milling, and improved data acquisition schemes.

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.

A hallmark of neurodegenerative diseases (NDs) is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. However, studying the underlying cellular pathways and mechanisms has remained a challenge, as formation of many types of protein aggregates is asynchronous, with individual cells displaying distinct kinetics, thereby hindering rigorous time-course studies.

: a software package for large-scale cryo-electron tomography data preprocessing, community data sharing and collaborative computing.

Cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) are becoming the preferred methodologies for investigating subcellular and macromolecular structures in native or near-native environments. Although cryo-ET is amenable to a wide range of biological problems, these problems often have data-processing requirements that need to be individually optimized, precluding the notion of a one-size-fits-all processing pipeline. Cryo-ET data processing is also becoming progressively more complex due to the increasing number of packages for each processing step.

Mutual Dependence between Membrane Phase Separation and Bacterial Division Protein Dynamics in Synthetic Cell Models.

Cell membranes in bacteria are laterally polarized to produce specific environments for membrane proteins, e.g., proteins involved in cell division which accumulate at mid-cell or the cell poles.

Self-organized spatial targeting of contractile actomyosin rings for synthetic cell division.

A key challenge for bottom-up synthetic biology is engineering a minimal module for self-division of synthetic cells. Actin-based cytokinetic rings are considered a promising structure to produce the forces required for the controlled excision of cell-like compartments such as giant unilamellar vesicles (GUVs). Despite prior demonstrations of actin ring targeting to GUV membranes and myosin-induced constriction, large-scale vesicle deformation has been precluded due to the lacking spatial control of these contractile structures.

KANK1 promotes breast cancer development by compromising Scribble-mediated Hippo activation.

KANK1 is expressed in epithelial cells and connects focal adhesions with the adjacent cortical microtubule stabilizing complex. Although KANK1 was shown to suppress cancer cell growth in vitro, TCGA database points to high KANK1 levels associated with poor prognosis in a wide spectrum of human malignancies. Here, we address this discrepancy and report that KANK1 promotes proliferation and survival of PyMT-transformed mammary tumor cells in vivo.

Cross-platform DNA motif discovery and benchmarking to explore binding specificities of poorly studied human transcription factors.

A DNA sequence pattern, or "motif", is an essential representation of DNA-binding specificity of a transcription factor (TF). Any particular motif model has potential flaws due to shortcomings of the underlying experimental data and computational motif discovery algorithm. As a part of the Codebook/GRECO-BIT initiative, here we evaluated at large scale the cross-platform recognition performance of positional weight matrices (PWMs), which remain popular motif models in many practical applications.

Cryo-EM structure of single-layered nucleoprotein-RNA complex from Marburg virus.

Marburg virus (MARV) causes lethal hemorrhagic fever in humans, posing a threat to global health. We determined by cryogenic electron microscopy (cryo-EM) the MARV helical ribonucleoprotein (RNP) complex structure in single-layered conformation, which differs from the previously reported structure of a double-layered helix. Our findings illuminate novel RNP interactions and expand knowledge on MARV genome packaging and nucleocapsid assembly, both processes representing attractive targets for the development of antiviral therapeutics against MARV disease.

Crystalline Assemblies of DNA Nanostructures and Their Functional Properties.

Self-assembly presents a remarkable approach for creating intricate structures by positioning nanomaterials in precise locations, with control over molecular interactions. For example, material arrays with interplanar distances similar to the wavelength of light can generate structural color through complex interactions like scattering, diffraction, and interference. Moreover, enzymes, plasmonic nanoparticles, and luminescent materials organized in periodic lattices are envisioned to create functional materials with various applications.

The conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation.

HIV-1 particles are released in an immature, non-infectious form. Proteolytic cleavage of the main structural polyprotein Gag into functional domains induces rearrangement into mature, infectious virions. In immature virus particles, the Gag membrane binding domain, MA, forms a hexameric protein lattice that undergoes structural transition upon cleavage into a distinct, mature MA lattice.

A physical model for M1-mediated influenza A virus assembly.

Influenza A virus particles assemble at the plasma membrane of infected cells. During assembly all components of the virus come together in a coordinated manner to deform the membrane into a protrusion eventually forming a new, membrane-enveloped virus. Here, we integrate recent molecular insights of this process, particularly concerning the structure of the matrix protein 1 (M1), within a theoretical framework describing the mechanics of virus assembly.

A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation.

Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe.