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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Linking secretion and cytoskeleton in immunity– a case for Arabidopsis TGNap1

In plants, robust defense depends on the efficient and resilient trafficking supply chains to the site of pathogen attack. Though the importance of intracellular trafficking in plant immunity has been well established, a lack of clarity remains regarding the contribution of the various trafficking pathways in transporting immune-related proteins. We have recently identified a trans-Golgi network protein, TGN-ASSOCIATED PROTEIN 1 (TGNap1), which functionally links post-Golgi vesicles with the cytoskeleton to transport immunity-related proteins in the model plant species Arabidopsis thaliana. We propose new hypotheses on the various functional implications of TGNap1 and then elaborate on the surprising heterogeneity of TGN vesicles during immunity revealed by the discovery of TGNap1 and other TGN-associated proteins in recent years.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

SEC ‐ SAXS / MC Ensemble Structural Studies of the Microtubule Binding Protein Cdt1 Show Monomeric, Folded‐Over Conformations

ABSTRACT Cdt1 is a mixed folded protein critical for DNA replication licensing and it also has a “moonlighting” role at the kinetochore via direct binding to microtubules and the Ndc80 complex. However, it is unknown how the structure and conformations of Cdt1 could allow it to participate in these multiple, unique sets of protein complexes. While robust methods exist to study entirely folded or unfolded proteins, structure–function studies of combined, mixed folded/disordered proteins remain challenging. In this work, we employ orthogonal biophysical and computational techniques to provide structural characterization of mitosis‐competent human Cdt1. Thermal stability analyses shows that both folded winged helix domains1 are unstable. CD and NMR show that the N‐terminal and linker regions are intrinsically disordered. DLS shows that Cdt1 is monomeric and polydisperse, while SEC‐MALS confirms that it is monomeric at high concentrations, but without any apparent inter‐molecular self‐association. SEC‐SAXS enabled computational modeling of the protein structures. Using the program SASSIE, we performed rigid body Monte Carlo simulations to generate a conformational ensemble of structures. We observe that neither fully extended nor extremely compact Cdt1 conformations are consistent with SAXS. The best‐fit models have the N‐terminal and linker disordered regions extended into the solution and the two folded domains close to each other in apparent “folded over” conformations. We hypothesize the best‐fit Cdt1 conformations could be consistent with a function as a scaffold protein that may be sterically blocked without binding partners. Our study also provides a template for combining experimental and computational techniques to study mixed‐folded proteins.

Cell Biology↗
NASA NTRS1994

A fiber matrix model for fluid flow and streaming potentials in the canaliculi of an osteon

A theoretical model is developed to predict the fluid shear stress and streaming potential at the surface of osteocytic processes in the lacunar-canalicular porosity of an osteon when the osteon is subject to mechanical loads that are parallel or perpendicular to its axis. The theory developed in Weinbaum et al. (31) for the flow through a proteoglycan matrix in a canaliculus is employed in a poroelastic model for the osteon. Our formulation is a generalization of that of Petrov et al. (17). Our model predicts that, in order to satisfy the measured frequency dependence of the phase and magnitude of the SGP in macroscopic bone samples, the fiber spacing in the fluid annulus must lie in the narrow range 6-7 nm typical of the spacing of GAG sidechains along a protein monomer. The model predictions for the local SGP profiles in the osteon agree with the experimental observations of Starkebaum et al. (24). The theory predicts that the pore pressure relaxation time, tau d, for a 150-300 microns diameter osteon with the foregoing matrix structure is approximately 0.03-0.13 sec, and that the amplitude of the mean fluid shear stress on the membrane of the osteocytic process at the mean areal radius of the osteon has a maximum at 28 Hz if tau d = 0.06 sec. This maximum, which is independent of the magnitude of the loading, could be important in vivo since the recent experiments of Turner et al. (28) and McLeod et al. (15) have a peak in the strain frequency spectrum between 20 and 30 Hz that also appears to be independent of the type (magnitude) of loading. Numerical predictions for the amplitude of the average fluid shear stress on the osteocytic membrane at the mean areal radius of the osteon show that the fluid shear stress associated with the low amplitude 20-30 Hz spectral strain component is at least as large as the average fluid shear stress associated with the high amplitude 1 Hz stride component, although the latter loading is an order of magnitude larger, and has a magnitude that lies within the middle of the range, 6-30 dynes/cm2, where fluid shear stresses in tissue culture studies with osteoblast monolayers have elicited an intracellular Ca++ response (31). The implications of these results for intracellular electrical communication are discussed.

Non-NASA Center↗
NASA NTRS1999

Progress toward an explicit mechanistic model for the light-driven pump, bacteriorhodopsin

Recent crystallographic information about the structure of bacteriorhodopsin and some of its photointermediates, together with a large amount of spectroscopic and mutational data, suggest a mechanistic model for how this protein couples light energy to the translocation of protons across the membrane. Now nearing completion, this detailed molecular model will describe the nature of the steric and electrostatic conflicts at the photoisomerized retinal, as well as the means by which it induces proton transfers in the two half-channels leading to the two membrane surfaces, thereby causing unidirectional, uphill transport.

Review, Tutorial↗
DOE OSTI2024

Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast

The recognition of the 5′ splice site (5′ ss) is one of the earliest steps of pre-mRNA splicing. To better understand, the mechanism and regulation of 5′ ss recognition, we selectively humanized components of the yeast U1 (yU1) snRNP to reveal the function of these components in 5′ ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yU1 snRNA and the 5′ ss RNA duplex. We replaced the zinc-finger (ZnF) domain of yeast U1C (yU1C) with its human counterpart, which resulted in a cold-sensitive growth phenotype and moderate splicing defects. We next added an auxin-inducible degron to yeast Luc7 (yLuc7) protein (to mimic the lack of Luc7Ls in human U1 snRNP). We found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of Prp40 and Snu71 (two other essential yU1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe 2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7–Prp40–Snu71 trimer into yU1 snRNP, and splicing plays a major role in the regulation of mitochondrial function in yeast.

Biochemistry & Molecular Biology↗
DOE OSTI2026

Development of an Amine Oxide Polyzwitterion Brush Martini Model with Polarizable Water and Ions

Abstract In order to accurately simulate the fouling process of proteins onto polyzwitterion brushes, models that accurately capture the hydration properties and chain conformations of such brushes must first be established. We developed a Martini coarse-grained (CG) model for amine oxide polyzwitterion (PNOMA) brushes, a promising class of antifouling materials, in polarizable water and ions by fitting to all-atom bond and angle distributions, monomer hydration free energy, monomer–monomer distance potential of mean force (PMF), and monomer–salt radial distribution functions (RDFs). Martini 2.2P was selected for compatibility with the established polarizable water and ion models. For comparison with PNOMA, we also constructed models for conventional sulfobetaine (PSBMA) and phosphorylcholine (PMPC) polyzwitterions and the polycation PMETAC using established nonbonded bead types from the literature and refitting bond and angle potentials. We simulated each polymer brush chemistry for varying grafting density and chain length, validating brush height scaling relations against experimental data. The CG models captured the relative hydration strengths among different polyzwitterion chemistries, and brush heights extrapolated to higher molecular weights are in agreement with experimental ellipsometry data. We find that chain swelling of the superhydrophilic PNOMA brushes lies between that of the traditional polyzwitterions PSBMA/PMPC and the polycation PMETAC. For PNOMA brushes in NaCl solution, simulated brush height decreases with salt concentration due to the selectively strong interactions between amine oxide and sodium ions.

Walker, Christopher C. [Oak Ridge National Laborat↗
NASA NTRS2000

Fluorescence Studies of Protein Crystal Nucleation

One of the most powerful and versatile methods for studying molecules in solution is fluorescence. Crystallization typically takes place in a concentrated solution environment, whereas fluorescence typically has an upper concentration limit of approximately 1 x 10(exp -5)M, thus intrinsic fluorescence cannot be employed, but a fluorescent probe must be added to a sub population of the molecules. However the fluorescent species cannot interfere with the self-assembly process. This can be achieved with macromolecules, where fluorescent probes can be covalently attached to a sub population of molecules that are subsequently used to track the system as a whole. We are using fluorescence resonance energy transfer (FRET) to study the initial solution phase self-assembly process of tetragonal lysozyme crystal nucleation, using covalent fluorescent derivatives which crystallize in the characteristic P432121 space group. FRET studies are being carried out between cascade blue (CB-lys, donor, Ex 376 nm, Em 420 nm) and lucifer yellow (LY-lys, acceptor, Ex 425 nm, Em 520 nm) asp101 derivatives. The estimated R0 for this probe pair, the distance where 50% of the donor energy is transferred to the acceptor, is approximately 1.2 nm, compared to 2.2 nm between the side chain carboxyls of adjacent asp101's in the crystalline 43 helix. The short CB-lys lifetime (approximately 5 ns), coupled with the large average distances between the molecules ((sup 3) 50 nm) in solution, ensure that any energy transfer observed is not due to random diffusive interactions. Addition of LY-lys to CB-lys results in the appearance of a second, shorter lifetime (approximately 0.2 ns). Results from these and other ongoing studies will be discussed in conjunction with a model for how tetragonal lysozyme crystals nucleate and grow, and the relevance of that model to microgravity protein crystal growth

Pusey, Marc L.↗
DOE OSTI2025

SFold v0.1

This is a scientific software package to integrate Small Angle X-ray Scattering (SAXS) experimental data into OpenFold deep learning models to improve protein structure prediction.

Prince, Stephanie [Lawrence Berkeley National Labo↗
DOE OSTI2025

Accuracy-Based Annotation Quality Score (ABAQS) v1.0

Assessing genome annotation quality is crucial for downstream analyses, but current methods are inadequate for eukaryotes. We present Accuracy-Based Annotation Quality Score (ABAQS), a novel, minimal-data-driven method that comprehensively assesses annotation quality. ABAQS evaluates multiple factors, including genome completeness, gene model validity, and protein profile accuracy, outperforming other metrics like BUSCO and PSAURON. We applied ABAQS to over 2500 eukaryotic genomes and showed its robustness and effectiveness in evaluating genome annotation quality, making it a valuable tool for researchers working with genomic data. ABAQS reveals significant variation in annotation quality and highlights the importance of filtering in improving annotation quality and accuracy.

Haridas, Sajeet [Lawrence Berkeley National Labora↗
DOE OSTI2024

Relationship Between Radiation Dose and Markers of Insulin Resistance and Inflammation in Atomic Bomb Survivors

Abstract Context In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation; however, no studies have examined low to moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors. Objective To examine the association between radiation dose and markers of inflammation and insulin resistance. Methods This study investigated 3152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance. Results Radiation dose was significantly and positively associated with levels of C-reactive protein, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and high-density lipoprotein cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance. Conclusion Insulin resistance might be a possible factor in radiation-related diabetes incidence in A-bomb survivors.

Endocrinology & Metabolism↗
NASA NTRS1982

Effect of limb immobilization on skeletal muscle

Current knowledge and questions remaining concerning the effects of limb immobilization on skeletal muscle is reviewed. The most dramatic of these effects is muscle atrophy, which has been noted in cases of muscles fixed at or below their resting length. Immobilization is also accompanied by a substantial decrease in motoneuronal discharges, which results in the conversion of slow-twitch muscle to muscle with fast-twitch characteristics. Sarcolemma effects include no change or a decrease in resting membrane potential, the appearance of extrajunctional acetylcholine receptors, and no change in acetylcholinesterase activity. Evidence of changes in motoneuron after hyperpolarization characteristics suggests that the muscle inactivity is responsible for neuronal changes, rather than vice versa. The rate of protein loss from atrophying muscles is determined solely by the first-order rate constant for degradation. Various other biochemical and functional changes have been noted, including decreased insulin responsiveness and protein synthesis. The model of limb immobilization may also be useful for related studies of muscle adaptation.

Booth, F. W.↗
NASA NTRS1995

Crystal Growth and Spectroscopy of Diglycine

Raman and infrared spectra have been obtained for alpha-diglycine (C4H8N2O3) single crystals. These dipeptide crystals are being grown as a models system for protein crystal growth studies. There have been previous Raman measurements on diglycine powder samples recorded, but there is no reference to measurements on oriented diglycine single crystals. Diglycine can grow in one of three forms, alpha, beta, or gamma.

Taylor, Taravia M.↗
NASA NTRS1998

Modeling the Growth Rates of Tetragonal Lysozyme Crystal Faces

The measured macroscopic growth rates of the (110) and (101) faces of tetragonal lysozyme show an unexpectedly complex dependence on the supersaturation. The growth rates decay asymptotically to zero when the supersaturation is lowered to zero and increase rapidly when the supersaturation is increased. When supersaturations are increased still further the growth rates attain a maximum before starting to decrease. However, growth of these crystals is known to proceed by the classical dislocation and 2D nucleation growth mechanisms. This anomaly can be explained if growth is assumed to occur not by monomer units but by lysozyme aggregates. Analysis of the molecular packing of these crystals revealed that they were constructed of strongly bonded 4(sub 3) helices, while weaker bonds were responsible for binding the helices to each other. It follows that during crystal growth the stronger bonds are formed before the weaker ones. Thus, the growth of these crystals could be viewed as a two step process: aggregate growth units corresponding to the 4(sub 3) helix are first formed in the bulk solution by stronger intermolecular bonds and then attached to the crystal face by weaker bonds on dislocation hillocks or 2D islands. This will lead to a distribution of aggregates in the solution with monomers and lower order aggregates being predominant at low supersaturations and higher order aggregates being predominant at high supersaturations. If the crystal grows mostly by higher order aggregates, such as tetramers and octamers, it would explain the anomalous dependence of the growth rates on the supersaturation. Besides the analysis of molecular packing, a comprehensive analysis of the measured (110) and (101) growth rates was also undertaken in this study. The distribution of aggregates in lysozyme nutrient solutions at various solution conditions were determined from reversible aggregation reactions at equilibrium. The supersaturation was defined for each aggregate species with respect to its concentration at saturation in order to apply growth rate models to this process. The measured growth rates were then compared with the predicted ones from several dislocation and 2D nucleation growth models, employing tetramer and octamer growth units in polydisperse solutions and monomer units in monodisperse solutions. For the (110) face, the calculations consistently showed that the measured growth rates followed the expected model relations with octamer growth units. For the (101) face, it is not possible to obtain a clear agreement between the predicted and measured growth rates for a single growth unit as done for the (110) face. However, the calculations do indicate that the average size of the growth unit is between a tetramer and an octamer. This suggests that tetramers, octamers and other intermediate size growth units all participate in the growth process for this face. These calculations show that it is possible to model the macroscopic protein crystal growth rates if the molecular level processes can be account for, particularly protein aggregation processes in the bulk solution. Our recent investigations of tetragonal lysozyme crystals employing high resolution atomic force microscopy scans have further confirmed the growth of these crystals by aggregate growth units corresponding to 4(sub 3) helices.

Li, Meirong↗
NASA NTRS2003

The Effect of Simulated Microgravity Environment of RWV Bioreactors on Surface Reactions and Adsorption of Serum Proteins on Bone-bioactive Microcarriers

Biomimetically modified bioactive materials with bone-like surface properties are attractive candidates for use as microcarriers for 3-D bone-like tissue engineering under simulated microgravity conditions of NASA designed rotating wall vessel (RWV) bioreactors. The simulated microgravity environment is attainable under suitable parametric conditions of the RWV bioreactors. Ca-P containing bioactive glass (BG), whose stimulatory effect on bone cell function had been previously demonstrated, was used in the present study. BG surface modification via reactions in solution, resulting formation of bone-like minerals at the surface and adsorption of serum proteins is critical for obtaining the stimulatory effect. In this paper, we report on the major effects of simulated microgravity conditions of the RWV on the BG reactions surface reactions and protein adsorption in physiological solutions. Control tests at normal gravity were conducted at static and dynamic conditions. The study revealed that simulated microgravity remarkably enhanced reactions involved in the BG surface modification, including BG dissolution, formation of bone-like minerals at the surface and adsorption of serum proteins. Simultaneously, numerical models were developed to simulate the mass transport of chemical species to and from the BG surface under normal gravity and simulated microgravity conditions. The numerical results showed an excellent agreement with the experimental data at both testing conditions.

Radin, Shula↗
NASA NTRSDate not supplied

The Light Microscopy Module A Facility Overview-History and Science

We will share a brief history and provide a science overview of the many accomplishments of the Light Microscopy Module (LMM), a microscope that has been operating in the microgravity environment of the International Space Station (ISS) since 2010. It will be removed in October 2021. It was initially outfitted for the Constrained Vapor Bubble – Wickless Heat Pipe experiment. It was later reconfigured and upgraded many times to support a broad portfolio of Physical science and Biological experiments including: Complex Fluids, Colloids, Macro-Molecular Biophysics, Protein Crystals, and Plant Biology. The LMM has enabled many significant studies and discoveries and has seen its fair share of pleasant surprises. These include recording order arising out of disorder, e.g., systems of colloids that were glasses on Earth crystallizing to form large defect-free crystals, nematic ordering of elliptical colloids, and colloidal-polymer systems crystallizing. The LMM science teams have also seen how to improve product stabilizers once the effects of sedimentation on Earth were removed; they were able to see which tagged genes express in plants when gravity is removed, telling them which genes are essential for growing plants in space; they’ve tested protein crystal growth models; checked models for creating bijel electrodes that turn batteries into fast-charging supercapacitors; tested many forms of colloidal self-assembly: including those using depletion attraction, magnetic fields, and critical Casimir forces; they’ve observed explosive bubble nucleation in a wickless heat pipe, and much more. This work has been supported by the NASA Biological and Physical Sciences (BPS) Division and the ISS Program Office, Johnson Space Center Code OZ and Code OB, the Center for the Advancement of Science in Space (CASIS) / ISS National Lab, EPSCoR, and ISS international partners from ESA – the Netherlands and Italy, CSA, JAXA and S. Korea, and by Space Act Agreements with Procter and Gamble (P&G).

Colloids↗
DOE OSTI2025

PET-FBA: A lightweight enzyme allocation and thermodynamics-constrained flux analysis approach to explore Escherichia coli metabolic adaptation to intracellular acidification

Escherichia coli employs diverse strategies to adapt to acidic environments that disrupt enzyme activity and the thermodynamic feasibility of essential reactions. To understand the impact of pH stress on cell metabolism, we present the PET-FBA (pH-, Enzyme protein allocation-, and Thermodynamics-constrained Flux Balance Analysis) framework. PET-FBA extends genome-scale modeling by integrating enzyme protein costs and reaction Gibbs free energy changes. Additionally, by incorporating pH-dependent enzyme kinetics in response to intracellular acidification, this framework enables the simulation of E. coli's metabolic adjustments across varying external pH levels. The model's accuracy is validated by comparing in silico growth simulations with experimental measurements under both anaerobic and aerobic conditions, as well as in silico gene knockouts of essential genes. By explicitly incorporating pH effects, our model accurately replicates the metabolic shift towards lactate production as the primary fermentation product at low pH in anaerobic conditions. This shift is only predicted when enzyme kinetics are dynamically adjusted as a function of pH. Further analysis revealed that this shift can be attributed to the reduced protein efficiency of the acetyl-CoA branch compared to lactate dehydrogenase under acidic stress, which then becomes crucial for maintaining NAD regeneration and cell growth at low pH. Furthermore, we identified strategies for enhancing cell growth under acidic anaerobic conditions by improving the enzyme activity of lactate dehydrogenase and pyruvate formate lyase, which increases NAD production efficiency and reduces enzyme protein allocation costs. Designed as a lightweight yet versatile framework, PET-FBA enables efficient genome-scale metabolic analysis. Using E. coli as a model system, our framework provides a systematic approach to understanding metabolic responses to environmental stress, pinpointing key metabolic bottlenecks, and identifying potential targets for strain optimization.

42 ENGINEERING↗
DOE OSTI2024

Structure-aware annotation of leucine-rich repeat domains

Protein domain annotation is typically done by predictive models such as HMMs trained on sequence motifs. However, sequence-based annotation methods are prone to error, particularly in calling domain boundaries and motifs within them. These methods are limited by a lack of structural information accessible to the model. With the advent of deep learning-based protein structure prediction, existing sequenced-based domain annotation methods can be improved by taking into account the geometry of protein structures. We develop dimensionality reduction methods to annotate repeat units of the Leucine Rich Repeat solenoid domain. The methods are able to correct mistakes made by existing machine learning-based annotation tools and enable the automated detection of hairpin loops and structural anomalies in the solenoid. The methods are applied to 127 predicted structures of LRR-containing intracellular innate immune proteins in the model plant Arabidopsis thaliana and validated against a benchmark dataset of 172 manually-annotated LRR domains.

Xu, Boyan↗