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    Real-Time Nanopore-Based Recognition of Protein Translocation Success.
    Biophys J 2018 Jan 12. Epub 2018 Jan 12.
    Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Electronic address:
    A growing number of new technologies are supported by a single- or multi-nanopore architecture for capture, sensing, and delivery of polymeric biomolecules. Nanopore-based single-molecule DNA sequencing is the premier example. This method relies on the uniform linear charge density of DNA, so that each DNA strand is overwhelmingly likely to pass through the nanopore and across the separating membrane. Read More

    The Starch Utilization System Assembles around Stationary Starch-Binding Proteins.
    Biophys J 2018 Jan 12. Epub 2018 Jan 12.
    Department of Chemistry, University of Michigan, Ann Arbor, Michigan. Electronic address:
    Bacteroides thetaiotaomicron (Bt) is a prominent member of the human gut microbiota with an extensive capacity for glycan harvest. This bacterium expresses a five-protein complex in the outer membrane, called the starch utilization system (Sus), which binds, degrades, and imports starch into the cell. Sus is a model system for the many glycan-targeting polysaccharide utilization loci found in Bt and other members of the Bacteroidetes phylum. Read More

    Role of Phosphorylation in Moesin Interactions with PIP2-Containing Biomimetic Membranes.
    Biophys J 2018 Jan;114(1):98-112
    CNRS UMR 5628 (LMGP), University Grenoble Alpes, CEA, CNRS, Grenoble, France; Institut National Polytechnique de Grenoble, University Grenoble Alpes, CEA, CNRS, Grenoble, France. Electronic address:
    Moesin, a protein of the ezrin, radixin, and moesin family, which links the plasma membrane to the cytoskeleton, is involved in multiple physiological and pathological processes, including viral budding and infection. Its interaction with the plasma membrane occurs via a key phosphoinositide, the phosphatidyl(4,5)inositol-bisphosphate (PIP2), and phosphorylation of residue T558, which has been shown to contribute, in cellulo, to a conformationally open protein. We study the impact of a double phosphomimetic mutation of moesin (T235D, T558D), which mimics the phosphorylation state of the protein, on protein/PIP2/microtubule interactions. Read More

    LRET Determination of Molecular Distances during pH Gating of the Mammalian Inward Rectifier Kir1.1b.
    Biophys J 2018 Jan;114(1):88-97
    Department of Physiology and Biophysics, The Chicago Medical School, Rosalind Franklin University, North Chicago, Illinois. Electronic address:
    Gating of the mammalian inward rectifier Kir1.1 at the helix bundle crossing (HBC) by intracellular pH is believed to be mediated by conformational changes in the C-terminal domain (CTD). However, the exact motion of the CTD during Kir gating remains controversial. Read More

    Ion Specificity and Nonmonotonic Protein Solubility from Salt Entropy.
    Biophys J 2018 Jan;114(1):76-87
    Department of Physics, Kansas State University, Manhattan, Kansas. Electronic address:
    The addition of salt to protein solutions can either increase or decrease the protein solubility, and the magnitude of this effect depends on the salt used. We show that these effects can be captured using a theory that includes attractive and repulsive electrostatic interactions, nonelectrostatic protein-ion interactions, and ion-solvent interactions via an effective solvated ion radius. We find that the ion radius has significant effects on the translational entropy of the salt, which leads to salt specificity in the protein solubility. Read More

    Effects of pH and Salt Concentration on Stability of a Protein G Variant Using Coarse-Grained Models.
    Biophys J 2018 Jan;114(1):65-75
    São Paulo State University (UNESP), Institute of Biosciences, Humanities and Exact Sciences (Ibilce), Campus São José do Rio Preto, Brazil. Electronic address:
    The importance of charge-charge interactions in the thermal stability of proteins is widely known. pH and ionic strength play a crucial role in these electrostatic interactions, as well as in the arrangement of ionizable residues in each protein-folding stage. In this study, two coarse-grained models were used to evaluate the effect of pH and salt concentration on the thermal stability of a protein G variant (1PGB-QDD), which was chosen due to the quantity of experimental data exploring these effects on its stability. Read More

    Using a FRET Library with Multiple Probe Pairs To Drive Monte Carlo Simulations of α-Synuclein.
    Biophys J 2018 Jan;114(1):53-64
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:
    We describe a strategy for experimentally-constraining computational simulations of intrinsically disordered proteins (IDPs), using α-synuclein, an IDP with a central role in Parkinson's disease pathology, as an example. Previously, data from single-molecule Förster Resonance Energy Transfer (FRET) experiments have been effectively utilized to generate experimentally constrained computational models of IDPs. However, the fluorophores required for single-molecule FRET experiments are not amenable to the study of short-range (<30 Å) interactions. Read More

    Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation.
    Biophys J 2018 Jan;114(1):40-52
    Department of Physics, State University of New York at Buffalo, Buffalo, New York. Electronic address:
    As a prototype cellular sensor, the TRPV1 cation channel undergoes a closed-to-open gating transition in response to various physical and chemical stimuli including noxious heat. Despite recent progress, the molecular mechanism of heat activation of TRPV1 gating remains enigmatic. Toward decrypting the structural basis of TRPV1 heat activation, we performed extensive molecular dynamics simulations (with cumulative simulation time of ∼11 μs) for the wild-type channel and a constitutively active double mutant at different temperatures (30, 60, and 72°C), starting from a high-resolution closed-channel structure of TRPV1 solved by cryo-electron microscopy. Read More

    Dynamic Structural Differences between Human and Mouse STING Lead to Differing Sensitivity to DMXAA.
    Biophys J 2018 Jan;114(1):32-39
    Discovery Sciences, Janssen Research and Development, San Diego, California.
    The stimulator-of-interferon-genes (STING) protein is involved in innate immunity. It has recently been shown that modulation of STING can lead to an aggressive antitumor response. DMXAA is an antitumor agent that had shown great promise in murine models but failed in human clinical trials. Read More

    Network Features and Dynamical Landscape of Naive and Primed Pluripotency.
    Biophys J 2018 Jan;114(1):237-248
    Stem Cell and Brain Research Institute, Univ. Lyon, Université Claude Bernard Lyon 1, INSERM, INRA, U1208, USC1361, Bron, France.
    Although the broad and unique differentiation potential of pluripotent stem cells relies on a complex transcriptional network centered around Oct4, Sox2, and Nanog, two well-distinct pluripotent states, called "naive" and "primed", have been described in vitro and markedly differ in their developmental potential, their expression profiles, their signaling requirements, and their reciprocal conversion. Aiming to determine the key features that segregate and coordinate these two states, data-driven optimization of network models is performed to identify relevant parameter regimes and reduce network complexity to its core structure. Decision dynamics of optimized networks is characterized by signal-dependent multistability and strongly asymmetric transitions among naive, primed, and nonpluripotent states. Read More

    Sharing of Phosphatases Promotes Response Plasticity in Phosphorylation Cascades.
    Biophys J 2018 Jan;114(1):223-236
    Modelling of Biological Networks Group, Institute of Molecular Biology (IMB), Mainz, Germany. Electronic address:
    Sharing of positive or negative regulators between multiple targets is frequently observed in cellular signaling cascades. For instance, phosphatase sharing between multiple kinases is ubiquitous within the MAPK pathway. Here we investigate how such phosphatase sharing could shape robustness and evolvability of the phosphorylation cascade. Read More

    Collective Cell Migration in Embryogenesis Follows the Laws of Wetting.
    Biophys J 2018 Jan;114(1):213-222
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany; Center of Nonlinear Science (CeNoS), University of Münster, Münster, Germany.
    Collective cell migration is a fundamental process during embryogenesis and its initial occurrence, called epiboly, is an excellent in vivo model to study the physical processes involved in collective cell movements that are key to understanding organ formation, cancer invasion, and wound healing. In zebrafish, epiboly starts with a cluster of cells at one pole of the spherical embryo. These cells are actively spreading in a continuous movement toward its other pole until they fully cover the yolk. Read More

    Coevolutionary Landscape of Kinase Family Proteins: Sequence Probabilities and Functional Motifs.
    Biophys J 2018 Jan;114(1):21-31
    Center for Biophysics and Computational Biology, Department of Chemistry, and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania. Electronic address:
    The protein kinase catalytic domain is one of the most abundant domains across all branches of life. Although kinases share a common core function of phosphoryl-transfer, they also have wide functional diversity and play varied roles in cell signaling networks, and for this reason are implicated in a number of human diseases. This functional diversity is primarily achieved through sequence variation, and uncovering the sequence-function relationships for the kinase family is a major challenge. Read More

    Microtubule Polymerization and Cross-Link Dynamics Explain Axonal Stiffness and Damage.
    Biophys J 2018 Jan;114(1):201-212
    Department of Mechanical Engineering, Stanford University, Stanford, CA. Electronic address:
    Axonal damage is a critical indicator for traumatic effects of physical impact to the brain. However, the precise mechanisms of axonal damage are still unclear. Here, we establish a mechanistic and highly dynamic model of the axon to explore the evolution of damage in response to physical forces. Read More

    Dynamic Model for Characterizing Contractile Behaviors and Mechanical Properties of a Cardiomyocyte.
    Biophys J 2018 Jan;114(1):188-200
    State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang, China. Electronic address:
    Studies on the contractile dynamics of heart cells have attracted broad attention for the development of both heart disease therapies and cardiomyocyte-actuated micro-robotics. In this study, a linear dynamic model of a single cardiomyocyte cell was proposed at the subcellular scale to characterize the contractile behaviors of heart cells, with system parameters representing the mechanical properties of the subcellular components of living cardiomyocytes. The system parameters of the dynamic model were identified with the cellular beating pattern measured by a scanning ion conductance microscope. Read More

    Essential Role of the ε Subunit for Reversible Chemo-Mechanical Coupling in F1-ATPase.
    Biophys J 2018 Jan;114(1):178-187
    The University of Tokyo, Tokyo, Japan. Electronic address:
    F1-ATPase is a rotary motor protein driven by ATP hydrolysis. Among molecular motors, F1 exhibits unique high reversibility in chemo-mechanical coupling, synthesizing ATP from ADP and inorganic phosphate upon forcible rotor reversal. The ε subunit enhances ATP synthesis coupling efficiency to > 70% upon rotation reversal. Read More

    Label-free Imaging and Bending Analysis of Microtubules by ROCS Microscopy and Optical Trapping.
    Biophys J 2018 Jan;114(1):168-177
    Laboratory for Bio- and Nano-Photonics, Department of Microsystems Engineering, University of Freiburg, Freiburg, Germany. Electronic address:
    Mechanical manipulation of single cytoskeleton filaments and their monitoring over long times is difficult because of fluorescence bleaching or phototoxic protein degradation. The integration of label-free microscopy techniques, capable of imaging freely diffusing, weak scatterers such as microtubules (MTs) in real-time, and independent of their orientation, with optical trapping and tracking systems, would allow many new applications. Here, we show that rotating-coherent-scattering microscopy (ROCS) in dark-field mode can also provide strong contrast for structures far from the coverslip such as arrangements of isolated MTs and networks. Read More

    Changes in Cholesterol Level Alter Integrin Sequestration in Raft-Mimicking Lipid Mixtures.
    Biophys J 2018 Jan;114(1):158-167
    Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Integrated Nanosystems Development Institute, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana. Electronic address:
    The influence of cholesterol (CHOL) level on integrin sequestration in raft-mimicking lipid mixtures forming coexisting liquid-ordered (lo) and liquid-disordered (ld) lipid domains is investigated using complementary, single-molecule-sensitive, confocal detection methods. Systematic analysis of membrane protein distribution in such a model membrane environment demonstrates that variation of CHOL level has a profound influence on lo-ld sequestration of integrins, thereby exhibiting overall ld preference in the absence of ligands and lo affinity upon vitronectin addition. Accompanying photon-counting histogram analysis of integrins in the different model membrane mixtures shows that the observed changes of integrin sequestration in response to variations of membrane CHOL level are not associated with altering integrin oligomerization states. Read More

    Translational Entropy and DNA Duplex Stability.
    Biophys J 2018 Jan;114(1):15-20
    Biophysics Laboratories, School of Biology, University of Portsmouth, Portsmouth, United Kingdom. Electronic address:
    Investigation of folding/unfolding DNA duplexes of various size and composition by superprecise calorimetry has revised several long-held beliefs concerning the forces responsible for the formation of the double helix. It was established that: 1) the enthalpy and the entropy of duplex unfolding are temperature dependent, increasing with temperature rise and having the same heat capacity increment for CG and AT pairs; 2) the enthalpy of AT melting is greater than that of the CG pair, so the stabilizing effect of the CG pair in comparison with AT results not from its larger enthalpic contribution (as expected from its extra hydrogen bond), but from the larger entropic contribution of the AT pair that results from its ability to fix ordered water in the minor groove and release it upon duplex unfolding; 3) the translation entropy, resulting from the appearance of a new kinetic unit on duplex dissociation, determines the dependence of duplex stability on its length and its concentration (it is an order-of-magnitude smaller than predicted from the statistical mechanics of gases and is fully expressed by the stoichiometric correction term); 4) changes in duplex stability on reshuffling the sequence (the "nearest-neighbor effect") result from the immobilized water molecules fixed by AT pairs in the minor groove; and 5) the evaluated thermodynamic components permit a quantitative expression of DNA duplex stability. Read More

    Intrinsic Curvature-Mediated Transbilayer Coupling in Asymmetric Lipid Vesicles.
    Biophys J 2018 Jan;114(1):146-157
    University of Graz, Institute of Molecular Biosciences, Biophysics Division, NAWI Graz; BioTechMed-Graz, Graz, Austria. Electronic address:
    We measured the effect of intrinsic lipid curvature, J0, on structural properties of asymmetric vesicles made of palmitoyl-oleoyl-phosphatidylethanolamine (POPE; J0<0) and palmitoyl-oleoyl-phosphatidylcholine (POPC; J0∼0). Electron microscopy and dynamic light scattering were used to determine vesicle size and morphology, and x-ray and neutron scattering, combined with calorimetric experiments and solution NMR, yielded insights into leaflet-specific lipid packing and melting processes. Below the lipid melting temperature we observed strong interleaflet coupling in asymmetric vesicles with POPE inner bilayer leaflets and outer leaflets enriched in POPC. Read More

    K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions.
    Biophys J 2018 Jan;114(1):137-145
    Department of Chemistry, University of California Berkeley, Berkeley, California. Electronic address:
    Ras is a membrane-anchored signaling protein that serves as a hub for many signaling pathways and also plays a prominent role in cancer. The intrinsic behavior of Ras on the membrane has captivated the biophysics community in recent years, especially the possibility that it may form dimers. In this article, we describe results from a comprehensive series of experiments using fluorescence correlation spectroscopy and single-molecule tracking to probe the possible dimerization of natively expressed and fully processed K-Ras4B in supported lipid bilayer membranes. Read More

    Effect of H-Bond Donor Lipids on Phosphatidylinositol-3,4,5-Trisphosphate Ionization and Clustering.
    Biophys J 2018 Jan;114(1):126-136
    Department of Biological Sciences, Kent State University, Kent, Ohio.
    The phosphoinositide, phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), is a key signaling lipid in the inner leaflet of the cell plasma membrane, regulating diverse signaling pathways including cell growth and migration. In this study we investigate the impact of the hydrogen-bond donor lipids phosphatidylethanolamine (PE) and phosphatidylinositol (PI) on the charge and phase behavior of PI(3,4,5)P3. PE and PI can interact with PI(3,4,5)P3 through hydrogen-bond formation, leading to altered ionization behavior and charge distribution within the PI(3,4,5)P3 headgroup. Read More

    Effect of Ceramide Tail Length on the Structure of Model Stratum Corneum Lipid Bilayers.
    Biophys J 2018 Jan;114(1):113-125
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee; Multiscale Modeling and Simulation Center, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee. Electronic address:
    Lipid bilayers composed of non-hydroxy sphingosine ceramide (CER NS), cholesterol (CHOL), and free fatty acids (FFAs), which are components of the human skin barrier, are studied via molecular dynamics simulations. Since mixtures of these lipids exist in dense gel phases with little molecular mobility at physiological conditions, care must be taken to ensure that the simulations become decorrelated from the initial conditions. Thus, we propose and validate an equilibration protocol based on simulated tempering, in which the simulation takes a random walk through temperature space, allowing the system to break out of metastable configurations and hence become decorrelated from its initial configuration. Read More

    Warhammers for Peaceful Times.
    Biophys J 2018 Jan;114(1):1-2
    Department of Mechanical Engineering and Materials Science, Duke University, Durham, North Carolina. Electronic address:
    The Perkins group has recently developed a number of improved atomic force microscopy cantilevers using the focused ion beam technology. They compared the performance of these cantilevers in "real-life" biophysical single-molecule force spectroscopy measurements on protein unfolding, and the results of this comparison are reported in this issue of Biophysical Journal. Read More

    The Latest Twists in Chromatin Remodeling.
    Biophys J 2018 Jan 5. Epub 2018 Jan 5.
    Institute Lorentz for Theoretical Physics, Leiden University, Leiden, the Netherlands.
    In its most restrictive interpretation, the notion of chromatin remodeling refers to the action of chromatin-remodeling enzymes on nucleosomes with the aim of displacing and removing them from the chromatin fiber (the effective polymer formed by a DNA molecule and proteins). This local modification of the fiber structure can have consequences for the initiation and repression of the transcription process, and when the remodeling process spreads along the fiber, it also results in long-range effects essential for fiber condensation. There are three regulatory levels of relevance that can be distinguished for this process: the intrinsic sequence preference of the histone octamer, which rules the positioning of the nucleosome along the DNA, notably in relation to the genetic information coded in DNA; the recognition or selection of nucleosomal substrates by remodeling complexes; and, finally, the motor action on the nucleosome exerted by the chromatin remodeler. Read More

    Optocapacitive Generation of Action Potentials by Microsecond Laser Pulses of Nanojoule Energy.
    Biophys J 2017 Dec 19. Epub 2017 Dec 19.
    Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois; Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois. Electronic address:
    Millisecond pulses of laser light delivered to gold nanoparticles residing in close proximity to the surface membrane of neurons can induce membrane depolarization and initiate an action potential. An optocapacitance mechanism proposed as the basis of this effect posits that the membrane-interfaced particle photothermally induces a cell-depolarizing capacitive current, and predicts that delivering a given laser pulse energy within a shorter period should increase the pulse's action-potential-generating effectiveness by increasing the magnitude of this capacitive current. Experiments on dorsal root ganglion cells show that, for each of a group of interfaced gold nanoparticles and microscale carbon particles, reducing pulse duration from milliseconds to microseconds markedly decreases the minimal pulse energy required for AP generation, providing strong support for the optocapacitance mechanism hypothesis. Read More

    Benchmarks of Biomembrane Force Probe Spring Constant Models.
    Biophys J 2017 Dec;113(12):2842-2845
    Heart Research Institute, The University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia; Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia; Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia. Electronic address:

    Physical Mechanisms Driving Cell Sorting in Hydra.
    Biophys J 2017 Dec;113(12):2827-2841
    Department of Physics, University of California, San Diego, La Jolla, California; Division of Biological Sciences, University of California, San Diego, La Jolla, California. Electronic address:
    Cell sorting, whereby a heterogeneous cell mixture organizes into distinct tissues, is a fundamental patterning process in development. Hydra is a powerful model system for carrying out studies of cell sorting in three dimensions, because of its unique ability to regenerate after complete dissociation into individual cells. The physicists Alfred Gierer and Hans Meinhardt recognized Hydra's self-organizing properties more than 40 years ago. Read More

    Direct Numerical Simulation of Cellular-Scale Blood Flow in 3D Microvascular Networks.
    Biophys J 2017 Dec;113(12):2815-2826
    Mechanical and Aerospace Engineering Department, Rutgers, The State University of New Jersey, Piscataway, New Jersey. Electronic address:
    We present, to our knowledge, the first direct numerical simulation of 3D cellular-scale blood flow in physiologically realistic microvascular networks. The vascular networks are designed following in vivo images and data, and are comprised of bifurcating, merging, and winding vessels. Our model resolves the large deformation and dynamics of each individual red blood cell flowing through the networks with high fidelity, while simultaneously retaining the highly complex geometric details of the vascular architecture. Read More

    Two Distinct Fluorescence States of the Ligand-Induced Green Fluorescent Protein UnaG.
    Biophys J 2017 Dec;113(12):2805-2814
    Department of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan; Department of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo, Japan.
    UnaG is a recently discovered ligand-induced fluorescent protein that utilizes bound bilirubin (BR) as its fluorophore. The fluorescence of the UnaG-BR complex (holoUnaG) compares in quantum efficiency to that of enhanced green fluorescent protein, but it is superior in that the fluorophore formation is instantaneous and not dependent on oxygen; hence, much attention has been paid to UnaG as a new fluorescent probe. However, many important molecular properties of fluorescent probes remain unknown, such as the association/dissociation rates of BR, which determine the stability thereof, and the dispersibility of UnaG in aqueous solutions, which influence the functions of labeled proteins. Read More

    Mechanical Properties of a Drosophila Larval Chordotonal Organ.
    Biophys J 2017 Dec;113(12):2796-2804
    Faculty of Physics, Göttingen, Germany. Electronic address:
    Proprioception is an integral part of the feedback circuit that is essential for locomotion control in all animals. Chordotonal organs perform proprioceptive and other mechanosensory functions in insects and crustaceans. The mechanical properties of these organs are believed to be adapted to the sensory functions, but had not been probed directly. Read More

    Asymmetric Flows in the Intercellular Membrane during Cytokinesis.
    Biophys J 2017 Dec;113(12):2787-2795
    Department of Physics, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India. Electronic address:
    Eukaryotic cells undergo shape changes during their division and growth. This involves flow of material both in the cell membrane and in the cytoskeletal layer beneath the membrane. Such flows result in redistribution of phospholipid at the cell surface and actomyosin in the cortex. Read More

    Quantifying the Relationship between Single-Molecule Probes and Subunit Rotation in the Ribosome.
    Biophys J 2017 Dec;113(12):2777-2786
    Department of Physics, Northeastern University, Boston, Massachusetts. Electronic address:
    A major challenge in the study of biomolecular assemblies is to identify reaction coordinates that precisely monitor conformational rearrangements. This is central to the interpretation of single-molecule fluorescence resonance energy transfer measurements, where the observed dynamics depends on the labeling strategy. As an example, different probes of subunit rotation in the ribosome have provided qualitatively distinct descriptions. Read More

    Sarcomere Stiffness during Stretching and Shortening of Rigor Skeletal Myofibrils.
    Biophys J 2017 Dec;113(12):2768-2776
    Department of Kinesiology and Physical Education, McGill University, Montreal, Québec, Canada. Electronic address:
    In this study, we measured the stiffness of skeletal muscle myofibrils in rigor. Using a custom-built atomic force microscope, myofibrils were first placed in a rigor state then stretched and shortened at different displacements (0.1-0. Read More

    Single-Molecule Imaging of Wnt3A Protein Diffusion on Living Cell Membranes.
    Biophys J 2017 Dec;113(12):2762-2767
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; Department of Chemistry, Stanford University, Palo Alto, California. Electronic address:
    Wnt proteins are secreted, hydrophobic, lipidated proteins found in all animals that play essential roles in development and disease. Lipid modification is thought to facilitate the interaction of the protein with its receptor, Frizzled, but may also regulate the transport of Wnt protein and its localization at the cell membrane. Here, by employing single-molecule fluorescence techniques, we show that Wnt proteins associate with and diffuse on the plasma membranes of living cells in the absence of any receptor binding. Read More

    Composition Fluctuations in Lipid Bilayers.
    Biophys J 2017 Dec;113(12):2750-2761
    Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, Alberta, Canada. Electronic address:
    Cell membranes contain multiple lipid and protein components having heterogeneous in-plane (lateral) distribution. Nanoscale rafts are believed to play an important functional role, but their phase state-domains of coexisting phases or composition fluctuations-is unknown. As a step toward understanding lateral organization of cell membranes, we investigate the difference between nanoscale domains of coexisting phases and composition fluctuations in lipid bilayers. Read More

    A Loose Relationship: Incomplete H+/Sugar Coupling in the MFS Sugar Transporter GlcP.
    Biophys J 2017 Dec;113(12):2736-2749
    Max Planck Institute of Biophysics, Frankfurt/Main, Germany. Electronic address:
    The glucose transporter from Staphylococcus epidermidis, GlcPSe, is a homolog of the human GLUT sugar transporters of the major facilitator superfamily. Together with the xylose transporter from Escherichia coli, XylEEc, the other prominent prokaryotic GLUT homolog, GlcPSe, is equipped with a conserved proton-binding site arguing for an electrogenic transport mode. However, the electrophysiological analysis of GlcPSe presented here reveals important differences between the two GLUT homologs. Read More

    Interfacial Properties of NTAIL, an Intrinsically Disordered Protein.
    Biophys J 2017 Dec;113(12):2723-2735
    Aix-Marseille University, CNRS, Enzymologie Interfaciale et Physiologie de la Lipolyse UMR 7282, Marseille, France. Electronic address:
    Intrinsically disordered proteins (IDPs) lack stable secondary and tertiary structure under physiological conditions in the absence of their biological partners and thus exist as dynamic ensembles of interconverting conformers, often highly soluble in water. However, in some cases, IDPs such as the ones involved in neurodegenerative diseases can form protein aggregates and their aggregation process may be triggered by the interaction with membranes. Although the interfacial behavior of globular proteins has been extensively studied, experimental data on IDPs at the air/water (A/W) and water/lipid interfaces are scarce. Read More

    pKID Binds to KIX via an Unstructured Transition State with Nonnative Interactions.
    Biophys J 2017 Dec;113(12):2713-2722
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. Electronic address:
    Understanding the detailed mechanism of interaction of intrinsically disordered proteins with their partners is crucial to comprehend their functions in signaling and transcription. Through its interaction with KIX, the disordered pKID region of CREB protein is central in the transcription of cAMP responsive genes, including those involved in long-term memory. Numerous simulation studies have investigated these interactions. Read More

    Phosphorylation of the IDP KID Modulates Affinity for KIX by Increasing the Lifetime of the Complex.
    Biophys J 2017 Dec;113(12):2706-2712
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. Electronic address:
    Intrinsically disordered proteins (IDPs) are known to undergo a range of posttranslational modifications, but by what mechanism do such modifications affect the binding of an IDP to its partner protein? We investigate this question using one such IDP, the kinase inducible domain (KID) of the transcription factor CREB, which interacts with the KIX domain of CREB-binding protein upon phosphorylation. As with many other IDPs, KID undergoes coupled folding and binding to form α-helical structure upon interacting with KIX. This single site phosphorylation plays an important role in the control of transcriptional activation in vivo. Read More

    Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR.
    Biophys J 2017 Dec;113(12):2695-2705
    Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Electronic address:
    The human chemokine interleukin-8 (IL-8; CXCL8) is a key mediator of innate immune and inflammatory responses. This small, soluble protein triggers a host of biological effects upon binding and activating CXCR1, a G protein-coupled receptor, located in the cell membrane of neutrophils. Here, we describe 1H-detected magic angle spinning solid-state NMR studies of monomeric IL-8 (1-66) bound to full-length and truncated constructs of CXCR1 in phospholipid bilayers under physiological conditions. Read More

    Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E.
    Biophys J 2017 Dec;113(12):2682-2694
    Tata Institute of Fundamental Research, Hyderabad, Telangana, India. Electronic address:
    Among various isoforms of Apolipoprotein E (ApoE), the E4 isoform (ApoE4) is considered to be the strongest risk factor for Alzheimer's disease, whereas the E3 isoform (ApoE3) is neutral to the disease. Interestingly, the sequence of ApoE4 differs from its wild-type ApoE3 by a single amino acid C112R in the 299-amino-acid-long sequence. Hence, the puzzle remains: how a single-amino-acid difference between the ApoE3 and ApoE4 sequences can give rise to structural dissimilarities between the two isoforms, which can potentially lead to functional differences with significant pathological consequences. Read More

    Prediction of Thylakoid Lipid Binding Sites on Photosystem II.
    Biophys J 2017 Dec;113(12):2669-2681
    Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Groningen, the Netherlands.
    The thylakoid membrane has a unique lipid composition, consisting mostly of galactolipids. These thylakoid lipids have important roles in photosynthesis. Here, we investigate to what extent these lipids bind specifically to the Photosystem II complex. Read More

    A Hinged Signal Peptide Hairpin Enables Tat-Dependent Protein Translocation.
    Biophys J 2017 Dec;113(12):2650-2668
    Department of Molecular and Cellular Medicine, College of Medicine, The Texas A&M Health Science Center, Texas A&M University, College Station, Texas. Electronic address:
    The Tat machinery catalyzes the transport of folded proteins across the bacterial cytoplasmic membrane and the thylakoid membrane in plants. Using fluorescence quenching and cross-linking approaches, we demonstrate that the Escherichia coli TatBC complex catalyzes insertion of a pre-SufI signal peptide hairpin that penetrates about halfway across the membrane bilayer. Analysis of 512 bacterial Tat signal peptides using secondary structure prediction and docking algorithms suggest that this hairpin interaction mode is generally conserved. Read More

    Allosteric Modulation of Intact γ-Secretase Structural Dynamics.
    Biophys J 2017 Dec;113(12):2634-2649
    Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; NIH Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:
    As a protease complex involved in the cleavage of amyloid precursor proteins that lead to the formation of amyloid β fibrils implicated in Alzheimer's disease, γ-secretase is an important target for developing therapeutics against Alzheimer's disease. γ-secretase is composed of four subunits: nicastrin (NCT) in the extracellular (EC) domain, presenilin-1 (PS1), anterior pharynx defective 1, and presenilin enhancer 2 in the transmembrane (TM) domain. NCT and PS1 play important roles in binding amyloid β precursor proteins and modulating PS1 catalytic activity. Read More

    Myoglobin and α-Lactalbumin Form Smaller Complexes with the Biosurfactant Rhamnolipid Than with SDS.
    Biophys J 2017 Dec;113(12):2621-2633
    Interdisciplinary Nanoscience Center iNANO, Aarhus University, Aarhus C, Denmark; Department of Chemistry, Aarhus University, Aarhus C, Denmark. Electronic address:
    Biosurfactants (BSs) attract increasing attention as sustainable alternatives to petroleum-derived surfactants. This necessitates structural insight into how BSs interact with proteins encountered by current chemical surfactants. Thus, small-angle x-ray scattering (SAXS) has been used for studying the structures of complexes made of the proteins α-Lactalbumin (αLA) and myoglobin (Mb) with the biosurfactant rhamnolipid (RL). Read More

    Nanoscale Assembly of High-Mobility Group AT-Hook 2 Protein with DNA Replication Fork.
    Biophys J 2017 Dec;113(12):2609-2620
    Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address:
    High mobility group AT-hook 2 (HMGA2) protein is composed of three AT-hook domains. HMGA2 expresses at high levels in both embryonic stem cells and cancer cells, where it interacts with and stabilizes replication forks (RFs), resulting in elevated cell proliferation rates. In this study, we demonstrated that HMGA2 knockdown reduces cell proliferation. Read More

    Regulation of Contraction by the Thick Filaments in Skeletal Muscle.
    Biophys J 2017 Dec;113(12):2579-2594
    Randall Centre for Cell and Molecular Biophysics and BHF Centre of Research Excellence, King's College London, London, United Kingdom. Electronic address:
    Contraction of skeletal muscle cells is initiated by a well-known signaling pathway. An action potential in a motor nerve triggers an action potential in a muscle cell membrane, a transient increase of intracellular calcium concentration, binding of calcium to troponin in the actin-containing thin filaments, and a structural change in the thin filaments that allows myosin motors from the thick filaments to bind to actin and generate force. This calcium/thin filament mediated pathway provides the "START" signal for contraction, but it is argued that the functional response of the muscle cell, including the speed of its contraction and relaxation, adaptation to the external load, and the metabolic cost of contraction is largely determined by additional mechanisms. Read More

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