- by Bowen, A. E., Hadjivasiliou, Z.Developmental patterns can scale with size during growth, a phenomenon commonly attributed to morphogen scaling. Although patterning is orchestrated by gene regulatory networks (GRNs) activated by morphogens, how GRN dynamics interact with growth is not understood. We present a theoretical framework that integrates morphogen signalling, GRN dynamics, and tissue growth. We show that pattern scaling emerges from the interplay of GRN dynamics and growth, even in the absence of morphogen scaling. This relies on memory effects encoded in the GRNs, […]
- by Rathod, D., Parrott, K., Levitus, M.Protein oligomerization equilibria are central to many biological processes and are often highly sensitive to environmental conditions such as ionic strength, pH, and ligand binding. Quantitative characterization of these equilibria remains experimentally challenging because stable protein complexes frequently dissociate only at concentrations that are difficult to access with conventional biophysical methods. Fluorescence correlation spectroscopy (FCS) is uniquely suited to this problem, as it provides direct access to diffusion coefficients of fluorescently labeled proteins at nanomolar concentrations. However, the quantitative interpretation […]
- by Sauer, D. B., Song, J., Marden, J. J., Wang, B., Sowerby, K., Sudar, J. C., Rice, W. J., Wang, D.-N.The human sodium-citrate cotransporter NaCT imports various tri- and dicarboxylates into the cell as TCA cycle intermediates. This substrate uptake process is driven by an inward sodium gradient. The protein is a member of the Divalent Anion-Sodium Symporter (DASS) family. Whereas extensive biochemical and structural studies have been carried out for NaCT, how the substrate binding and translocation is coupled to the sodium gradient remains unclear. Here using single particle cryo-electron microscopy, we determined the structures of the human NaCT […]
- by Angelini, E., Leveille, C. L., Parent, S. E. P. E., Zaunbrecher, R. J., Barszczewski, T., Dixon, J. C., Mohammed, F. S., Morris, B., Yu, J., Arakaki, J., Dupar, R. J., Edmonds, J. H., Ehlers, E. A., Gamlin, C. R., Hedayati, M. J., Hookway, C., McCarley, J., Mogre, S. S., Phan, A., Roberts, B., Sanchez, E. E., Thottam, J. P., Wijesooriya, C. S., Yao, J., Kutys, M. L., Nazockdast, E., Wang, J., Theriot, J. A., Dalgin, G., Rafelski, S. M., Viana, M. P.Cell states are increasingly conceptualized as attractors of high-dimensional dynamical systems, yet quantitative approaches for integrating phenotypic information into this framework remain limited. Here, we take an image-based approach that combines unsupervised machine learning (ML) with timelapse imaging to extract and characterize the temporal dynamics of morphological features. Using a cell line with endogenously tagged VE-cadherin, we acquired brightfield and fluorescence timelapse images of human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) monolayers, which adopt distinct phenotypes at two different […]
- by Ye, M., Wang, Y.-H., Brogi, M., Parks, J. M., Kuo, K. M., Gumbart, J. C.Protein structure predictors achieve high single-state accuracy, but it remains unclear whether they can recover functionally relevant conformational ensembles or account for the presence of ligands and/or binding partners. Here, we benchmark AlphaFold3, Boltz-2, Chai-1, and BioEmu on four canonical multi-state proteins (Pf-MATE, LAO, SecA, and {beta}2AR), quantifying state bias and sampling breadth against experimental reference structures. Models frequently default to a dominant state represented in the PDB; small-molecule ligands have weak or inconsistent effects, while large protein partners drive […]
- by Swailem, M., Dill, K.What drove nucleic acids (NA) to associate with proteins (PR) at the Origins of Life? We reason from polymer physics and the Central Dogma (CD) that the fitness value of cooperating through a division of labor – NA for replication fidelity and PR for functional fitness – is much higher than for either polymer alone. Our model shows a Pareto Front, where NA and PR can bootstrap each other to achieve autocatalytic cooperativity towards biology.
- by Fernandes, J. B., Row, H., Shekhar, K., Mandadapu, K. K.Electrical signaling in biological systems is generally understood through the lens of single-channel biophysics, yet whether ensembles of ion channels can undergo cooperative opening and closing remains unclear. Here, we show that ensembles of voltage-gated ion channels can undergo bioelectrical order-disorder phase transitions driven by feedback between channel currents and local membrane voltage. When channels open, they carry ion-selective current that redistributes ions near the membrane and perturbs the transmembrane potential, thereby biasing the gating of nearby channels. This emergent […]
- by Kliegman, R., Grigorev, V., Zhang, Y.Biomolecular condensates are dynamic assemblies whose functions depend on continuous exchange of molecular components with the surrounding environment. While scaffold molecules drive phase separation and condensate architecture, many functional components are clients that are recruited through interactions with the scaffold-rich environment. Despite their prevalence, how client-scaffold interactions shape client exchange dynamics remains poorly understood. Here, we develop a reaction-diffusion model for client exchange in scaffold-driven condensates, in which clients switch between a scaffold-bound state and an unbound state. Bound clients […]
- by Muley, S., Agarwal, K., Ghosh, B.Cancer phenotypic plasticity drives invasion, treatment resistance, and relapse. Quantifying how cells dynamically couple morphology and migration in real time, without molecular labels, remains unsolved. Static molecular markers report on protein expression state rather than functional migratory behavior. Existing image-based metrics treat shape and migration as independent features, missing the coordinated coupling that defines plastic migratory states. We introduce Directional Shape Coupling (DSC), a quantitative metric purpose-built for live label-free imaging. DSC integrates movement direction consistency, shape deformation, and directional-shape […]
- by Riiska, C. A., Lee, M., Nemenman, Y., Thacker, G., Mendelson, J. R., Rieser, J. M.Animals navigating complex vertical environments must secure stable footholds, a challenge for species without feet. While arboreal climbing has evolved repeatedly in snakes, the physical mechanisms they use to scale broad, nearly flat surfaces remain poorly understood. By measuring three-dimensional body kinematics and per-contact forces on a smooth vertical wall with protruding posts, we show that cornsnakes climb by dynamically balancing forces across a highly redundant network of 5 to 16 simultaneous contacts–far exceeding the three contacts minimally required for […]
- by Zinga, K., Stachowiak, J., Ren, P.Liquid-liquid phase separation of proteins has been observed to occur on biological membranes, where it is thought to play a role in diverse cellular behaviors. Recent work has demonstrated colocalization between protein condensates on opposing leaflets of the bilayer, suggesting that protein phase separation may be coupled across the bilayer. However, the mechanism behind this coupling phenomenon remains poorly understood. Here we seek to understand the protein-protein and protein-membrane interactions that give rise to transbilayer coupling of protein condensates. We […]
- by Ma, N., Marie, M., Takase, D., del Torrent Masachs, C. L., Aguilar, J., Manglik, A., Matsunami, H., Vaidehi, N.Odorant receptors (ORs) belong to class A G protein coupled receptors that detect diverse small molecules, yet the steps that link odorant association to receptor mediated selectivity remains incompletely defined. Here we combined 1.26 milliseconds of all-atom odorant association Molecular Dynamics simulations with Markov state modeling and cell-based cAMP measurements to examine two human ORs receptors that recognize chemically distinct odorants. In the class I receptor OR51E2, propionate associates via two extracellular pathways gated for selectivity by residues in the […]
- Impact of chemotherapy on leukocyte stiffness -A longitudinal RT-DC study in a breast cancer patientby Kraeter, M., Herold, C., Taubenberger, A. V., Toepfner, N., Urbanska, M., Herbig, M., Link, T., Bornhaeuser, M., Guck, J., Jacobi, A.Background: The physical properties of leukocytes, such as cell size and stiffness, are critical for their circulation in microcapillary networks where rapid shape changes are required to squeeze through vascular constrictions. Alterations in the cells physical phenotype can promote venous thromboembolism (VTE), a common cause of death in cancer patients receiving chemotherapy. While biochemical VTE predictors are well studied, physical properties of blood cells receive less attention. Methods: Using real-time deformability cytometry (RT-DC), we monitored for the first time the […]
- by Zhang, Z., Zhou, M., Huang, Y., Wu, W., Jiao, H., Dai, M., Liang, T., Wen, J., Cheng, Z., Ma, X., Yuan, J., Hu, H., Shang, J., Marmorstein, R., Wei, X.Fatty Acid Transport Protein 2 (FATP2) couples fatty acid uptake to intracellular activation and is associated with pathological lipid accumulation in cancer and nonalcoholic fatty liver disease. Here, we present cryo-electron microscopy structures of human FATP2 across its reaction cycle. Our structures suggest that FATP2 recruits fatty acids directly from the membrane interface through a hydrophobic tunnel. Catalysis involves a ~130{degrees} rotation of the C-terminal domain, a transition trapped by the antihypertensive drugs isradipine and benidipine. Both drugs lock the […]
- by Biswas, I., Wang, Q., McCann, J. T., Tchesnokov, E. P., Nguyen, L., Saini, M., Cantero, J., Revalde, J. L., Gotte, M., Renslo, A., Neitz, R. J., Arkin, M. R., Arnold, E., Ruiz, F. X.Enterovirus D68 (EV-D68) is a non-polio picornavirus that has caused increasing rates of severe respiratory illness and acute flaccid myelitis in children worldwide this century. There are no approved vaccines or antivirals for EV-D68. Thus, we conducted a crystallographic fragment screening (CFS) and a high-throughput screening (HTS) biochemical assay against the EV-D68 RNA-dependent RNA polymerase 3D (3Dpol) to identify ligandable sites and non-nucleoside compounds that can spearhead anti-enteroviral drug discovery. The CFS, involving 650 fragments, identified 68 hit compounds (~10% […]
- by Mironov, S.Reaction diffusion (RD) systems play a fundamental role in numerous biochemical and biophysical processes. Here, we present a novel analytical framework for solving RD equations by applying the Wentzel Kramers Brillouin Jeffreys (WKBJ) formalism to Ca nanodomains generated by individual membrane channels, a widely used paradigm for intracellular Ca signaling. Previous models have primarily focused on stationary Ca nanodomains while neglecting diffusion and saturation of intracellular Ca buffers and sensors. In contrast, we derive analytical solutions without these simplifying assumptions. […]
- by Sharmin, S., Obermeyer, C., Maruthamuthu, V.Epithelial sheets must maintain robust barrier function while enduring severe mechanical deformations across various physiological environments. While baseline actomyosin contractility is understood to stabilize intercellular junctions and hence cell-cell contact integrity, how cell-generated active forces interact with external physical strain to dictate contact integrity remains poorly understood. In this study, we investigated the biophysical trade-offs between actomyosin contractility and barrier resilience when Madin-Darby Canine Kidney (MDCK) cell islands are subject to large stretch. In contrast to a high concentration (50 […]
- by Burke, P. J., Aghaei, P., Noh, S., Ramos-Silva, J. N., Jiang, M. J., chen, P.-L., Chen, Y., Goodarzinia, F., Usselman, R. J., Hemmer, P., Wallace, D. C.Summary ParagraphRecent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the proteins fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin–itself a central electron carrier in cellular metabolism–the magneto-fluorescence of a biological qubit is intrinsically coupled to the […]
- by Sanoria, M., Engra, G. M., Scita, G., Gov, N., Gopinathan, A.Directed migration along chemical gradients controls immune surveillance, development, and cancer invasion. However, the same chemical cue can produce different responses depending on its concentration and whether cells move alone or in groups. For example, in steep gradients, isolated malignant lymphocyte cells migrate away from the chemoattractant source, whereas clusters of the same cells continue to migrate toward it. Here, combining computational modeling and experimental observations, we show that this reversal is governed by coupled mechanisms acting across molecular, cellular, […]
- by Perez-Bertoldi, J. M., Dang, T. m. J., Golcuk, M., Lanska, E., Lopes, D., Henriot, V., Luo, J., Zhang, R., Ti, S.-C., Janke, C., Lansky, Z., Gur, M., Del Bene, F., Nogales, E.Microtubules support diverse cellular functions through regulation by microtubule-associated proteins and tubulin post-translational modification, yet how these two layers are mechanistically integrated remains unclear. -tubulin acetylation marks mechanically resilient microtubules, and its incorporation in defined microtubule sub-populations is not well understood. Here, we identify MTCL1 as a molecular link between microtubule stabilization and post-translational modification installation. We find that MTCL1 stabilizes microtubules and alters the luminal surface when copolymerized with tubulin, remodeling -tubulin and enhancing TAT-mediated tubulin acetylation through molecular […]
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