Articles Online Now

The Ras subfamily is the most extensively studied branch of the Ras superfamily, with 20% of all human tumors having activating mutations in one of the RAS genes. Recent studies have shown that the Ras/RalGDS/Ral pathway plays a more significant role in the progression of Ras-driven colon and pancreatic cancers than the Ras/Raf and Ras/PI3K pathways. In this study, we investigated the interaction between Ras and the Ras binding domain (RBD) of RalGDS using long-timescale molecular dynamics (MD) simulations.

Traditionally, cells have been classified by their type. Identifying cell types was deemed vital for understanding biological processes. More recently, cell type classification has been recognized as not good enough. Cells have many transient states that depend on their spatial environment and vary over time. The current cell states description recognizes that a cell is dynamic, varying over developmental time, location, senescence, and disease. While cell states refer to the functional behavior of the cells, biomacromolecular condensates are now recognized as the membraneless structures within them, which by concentrating functionally related proteins, make the function happen.

Infection with Lassa virus (LASV), an arenavirus endemic to West Africa, results in a viral hemorrhagic fever with high mortality rates and public health implications. The glycoprotein complex (GPC) is central to LASV’s infectivity as it mediates viral entry via membrane fusion. The fusion domain (FD, G260 – N295) facilitates the initiation of membrane fusion and, thus, the merging of the viral and host cell membranes in a pH-dependent fashion at the lysosomal membrane. The FD consists of two distinct regions: an N-terminal fusion peptide (FP, G260 – T274) and an internal fusion loop (FL, C279 – N295) that are connected by a short linker region (P275 – Y278).

Histone H1 is essential for higher-order chromatin organization, stabilizing linker DNA and bridging adjacent nucleosomes. To elucidate how cancer-associated mutations perturb this architectural hub, we constructed a comprehensive H1-centered interaction network by integrating structural and crosslinking mass spectrometry data, encompassing interactions among histones, DNA, and regulatory partners. Mapping cancer-associated mutations onto this network revealed significant enrichment at protein–protein interfaces and post-translational modification (PTM) sites, implicating disruption of histone modification crosstalk and network connectivity.

The remarkable capability of Tardigrade to survive under extreme conditions has been partially attributed to Dsup, an intrinsically disordered, highly positively charged protein. Dsup has been shown to bind to DNA in vitro, a property that has been associated with the capability of Dsup to exhibit stress-protective effects when expressed in mammalian cells. However, DNA binding of Dsup has not been visualized in living cells and expression of Dsup in different cell types was associated with either protective or detrimental effects.

Generalization through novel interpretations of the inner logic of the century-old Gibbs’ statistical thermodynamics is presented: i) Identifying kB → 0 as classical energetics without fluctuations, one directly derives a pair of thermodynamic variational formulae F(T)=E≥Eminmin{E−TS(E)}andS(E)=T>0min{ET−F(T)T},that dictate all the more familiar 1/T = dS(E)/dE, E = d{F(T)/T}/d(1/T), and S(E) = −dF(T)/dT in equilibrium, which is maintained by a duality symmetry with one-to-one relation between Teq(E) = arg minT{E/T − F(T)/T} and Eeq(T) = arg minE{E − TS(E)}.

Epithelial-mesenchymal transition (EMT) drives tubular atrophy and ECM remodeling during renal fibrosis. The cytokine transforming growth factor-beta 1 (TGF-β1) is a major regulator of EMT and other profibrotic cell processes that drive renal fibrosis. TGF-β1 signaling is upregulated in response to increased assembly of the ECM protein fibronectin (FN), creating a positive feedback loop that promotes chronic EMT and ECM remodeling. Investigating the role of TGF-β1-FN crosstalk in driving tubule damage is not easily probed via animal models or clinical investigations.

Protein phosphorylation is crucial in many cellular functions. Although the existence of functionally dispensable phosphosites is well recognized, previous estimation of dispensable content in the phosphoproteome has not quantitatively assessed how functional dispensability of a phosphosite is related to the degree of its perturbation specificity, i.e., the number of environmental perturbations where the phosphosite is phosphorylated. Here, we address this question by integrating a high-quality, perturbation-specific yeast phosphoproteome with site-specific evolutionary rate relative to adjacent residues of the site in the protein sequence (denoted “relative evolutionary rate”), a proxy for functional dispensability.

Vision begins with the photoisomerization of the chromophore 11-cis-retinal (11cR) to its all-trans form in visual rhodopsins. To regenerate visual rhodopsins, all-trans-retinal (atR) is re-isomerized to 11cR through a process known as the visual cycle in the eye. A key component of the vertebrate visual cycle is retinal G-protein-coupled receptor (RGR), which is a rhodopsin acting as a retinal photoisomerase that regenerates 11cR from atR by light. While the spectral properties of visual rhodopsins have been extensively characterized, those of RGRs among different animals remain poorly understood.

The formation of amyloid fibrils by the intrinsically disordered protein, α-synuclein, in human brain neurons and extracellular tissue is a hallmark of Parkinson's disease. While the stable protein β-structure in α-synuclein fibrils has been determined at high resolution, the status of the dynamically disordered domains, and their responses to in vivo confinement and small-molecule interactions, remain elusive. We use electron paramagnetic resonance spectroscopy of the spin probe, TEMPOL, co-localized with α-synuclein fibrils, and temperature-controlled, ice boundary confinement to characterize the physical and mechanical properties of the dynamically disordered protein and surrounding coupled solvent regions.

The timing of vaccine administration during the day significantly affects immunogenicity and vaccine efficacy, yet the mechanism governing the time-of-day dependent adaptive immunity and vaccine response remains elusive. In this study, we developed a comprehensive model for circadian-regulated adaptive immune responses that integrates recent findings on clock-immune interaction. The model was first benchmarked with experimental observations. We elucidated that the bistability arising from the self-enhancing homing process of antigen-presenting dendritic cells, combined with downstream rapid cell proliferation and the stability of memory T and B cells and antibodies, underlies the sustained differences observed in long-term vaccine efficacy.

Active nematics offer a versatile continuum framework for non-equilibrium collective phenomena, such as collective cell migration and tissue morphogenesis. However, the dynamic evolution of active nematics under complex multiphysics fields and the potential mechanism of how the defect dynamics control the distributions of field quantities remain elusive. Here, we establish a mechanochemical model that explicitly couples the orientational order with both morphogen concentration and hydrodynamic flow fields.