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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS1993

The 'tubulin-like' S1 protein of Spirochaeta is a member of the hsp65 stress protein family

A 65-kDa protein (called S1) from Spirochaeta bajacaliforniensis was identified as 'tubulin-like' because it cross-reacted with at least four different antisera raised against tubulin and was isolated, with a co-polymerizing 45-kDa protein, by warm-cold cycling procedures used to purify tubulin from mammalian brain. Furthermore, at least three genera of non-cultivable symbiotic spirochetes (Pillotina, Diplocalyx, and Hollandina) that contain conspicuous 24-nm cytoplasmic tubules displayed a strong fluorescence in situ when treated with polyclonal antisera raised against tubulin. Here we summarize results that lead to the conclusion that this 65-kDa protein has no homology to tubulin. S1 is an hsp65 stress protein homologue. Hsp65 is a highly immunogenic family of hsp60 proteins which includes the 65-kDa antigens of Mycobacterium tuberculosis (an active component of Freund's complete adjuvant), Borrelia, Treponema, Chlamydia, Legionella, and Salmonella. The hsp60s, also known as chaperonins, include E. coli GroEL, mitochondrial and chloroplast chaperonins, the pea aphid 'symbionin' and many other proteins involved in protein folding and the stress response.

NASA Discipline Exobiology↗
NASA NTRS2002

A calmodulin-binding/CGCG box DNA-binding protein family involved in multiple signaling pathways in plants

We reported earlier that the tobacco early ethylene-responsive gene NtER1 encodes a calmodulin-binding protein (Yang, T., and Poovaiah, B. W. (2000) J. Biol. Chem. 275, 38467-38473). Here we demonstrate that there is one NtER1 homolog as well as five related genes in Arabidopsis. These six genes are rapidly and differentially induced by environmental signals such as temperature extremes, UVB, salt, and wounding; hormones such as ethylene and abscisic acid; and signal molecules such as methyl jasmonate, H(2)O(2), and salicylic acid. Hence, they were designated as AtSR1-6 (Arabidopsis thaliana signal-responsive genes). Ca(2+)/calmodulin binds to all AtSRs, and their calmodulin-binding regions are located on a conserved basic amphiphilic alpha-helical motif in the C terminus. AtSR1 targets the nucleus and specifically recognizes a novel 6-bp CGCG box (A/C/G)CGCG(G/T/C). The multiple CGCG cis-elements are found in promoters of genes such as those involved in ethylene signaling, abscisic acid signaling, and light signal perception. The DNA-binding domain in AtSR1 is located on the N-terminal 146 bp where all AtSR1-related proteins share high similarity but have no similarity to other known DNA-binding proteins. The calmodulin-binding nuclear proteins isolated from wounded leaves exhibit specific CGCG box DNA binding activities. These results suggest that the AtSR gene family encodes a family of calmodulin-binding/DNA-binding proteins involved in multiple signal transduction pathways in plants.

Non-NASA Center↗
NASA NTRS1994

(abstract) Modeling Protein Families and Human Genes: Hidden Markov Models and a Little Beyond

We will first give a brief overview of Hidden Markov Models (HMMs) and their use in Computational Molecular Biology. In particular, we will describe a detailed application of HMMs to the G-Protein-Coupled-Receptor Superfamily. We will also describe a number of analytical results on HMMs that can be used in discrimination tests and database mining. We will then discuss the limitations of HMMs and some new directions of research. We will conclude with some recent results on the application of HMMs to human gene modeling and parsing.

Hidden Markov Models HMMs proteins computational m↗
NASA NTRS2018

On the Natural Structure of Amino Acid Patterns in Families of Protein Sequences

All known terrestrial proteins are coded as continuous strings of ≈20 amino acids. The patterns formed by the repetitions of elements in groups of finite sequences describes the natural architectures of protein families. We present a method to search for patterns and groupings of patterns in protein sequences using a mathematically precise definition for “repetition”, an efficient algorithmic implementation and a robust scoring system with no adjustable parameters. We show that the sequence patterns can be well-separated into disjoint classes according to their recurrence in nested structures. The statistics of the occurrences of patterns indicate that short repetitions are sufficient to account for the differences between natural families and randomized groups of sequences by more than 10 standard deviations, while contiguous sequence patterns shorter than 5 residues are effectively random in their occurrences. A small subset of patterns is sufficient to account for a robust ”familiarity” definition between arbitrary sets of sequences.

Pablo Turjanski↗
NASA NTRS2022

Free Energy Landscapes for Elucidating the Structural Consequences of Exon-20 mutations on the ErbB Family of Protein Kinases

The ErbB family of protein kinases plays an important role in major cellular functions and consequently mutations in the functional regions of these proteins are implicated in several types of cancer growths. To envision rational design of small molecule drugs that target the diseased proteins it is important to quantify the structural effects of the mutations, as some of these mutants render the protein resistant to tyrosine kinase inhibitors (TKIs). Herein we use advanced sampling techniques and long-timescale molecular dynamics simulations to predict the effect of major exon 20 mutations on the ErbB family, specifically EGFR and HER2 proteins. Exon 20 mutations have been clinically known to induce TKI resistance, though the mechanisms of such an effect is poorly understood. By mapping out the free energy landscape of the mutants and comparing them against the wild-type, we elucidate the structural differences in the binding pocket region that alter the nature of drug-protein interactions. We believe that these insights will play a pivotal role in developing small molecule drugs that overcome the TKI resistance.

Ashwin Ravichandran↗
NASA NTRS2019

Size and Structure of the Sequence Space of Repeat Proteins

The coding space of protein sequences is shaped by evolutionary constraints set by requirements of function and stability. We show that the coding space of a given protein family— the total number of sequences in that family—can be estimated using models of maximum entropy trained on multiple sequence alignments of naturally occurring amino acid sequences. We analyzed and calculated the size of three abundant repeat proteins families, whose members are large proteins made of many repetitions of conserved portions of *30 amino acids. While amino acid conservation at each position of the alignment explains most of the reduction of diversity relative to completely random sequences, we found that correlations between amino acid usage at different positions significantly impact that diversity. We quantified the impact of different types of correlations, functional and evolutionary, on sequence diversity. Analysis of the detailed structure of the coding space of the families revealed a rugged landscape, with many local energy minima of varying sizes with a hierarchical structure, reminiscent of frustrated energy landscapes of spin glass in physics. This clustered structure indicates a multiplicity of subtypes within each family and suggests new strategies for protein design.

Jacopo Marchi↗
NASA NTRS2002

Predicting functional divergence in protein evolution by site-specific rate shifts

Most modern tools that analyze protein evolution allow individual sites to mutate at constant rates over the history of the protein family. However, Walter Fitch observed in the 1970s that, if a protein changes its function, the mutability of individual sites might also change. This observation is captured in the "non-homogeneous gamma model", which extracts functional information from gene families by examining the different rates at which individual sites evolve. This model has recently been coupled with structural and molecular biology to identify sites that are likely to be involved in changing function within the gene family. Applying this to multiple gene families highlights the widespread divergence of functional behavior among proteins to generate paralogs and orthologs.

Review↗
NASA NTRS1983

The spatial distribution of fixed mutations within genes coding for proteins

An examination has been conducted of the extensive amino acid sequence data now available for five protein families - the alpha crystallin A chain, myoglobin, alpha and beta hemoglobin, and the cytochromes c - with the goal of estimating the true spatial distribution of base substitutions within genes that code for proteins. In every case the commonly used Poisson density failed to even approximate the experimental pattern of base substitution. For the 87 species of beta hemoglobin examined, for example, the probability that the observed results were from a Poisson process was the minuscule 10 to the -44th. Analogous results were obtained for the other functional families. All the data were reasonably, but not perfectly, described by the negative binomial density. In particular, most of the data were described by one of the very simple limiting forms of this density, the geometric density. The implications of this for evolutionary inference are discussed. It is evident that most estimates of total base substitutions between genes are badly in need of revision.

Holmquist, R.↗
NASA NTRS2001

Differential expression of members of the annexin multigene family in Arabidopsis

Although in most plant species no more than two annexin genes have been reported to date, seven annexin homologs have been identified in Arabidopsis, Annexin Arabidopsis 1-7 (AnnAt1--AnnAt7). This establishes that annexins can be a diverse, multigene protein family in a single plant species. Here we compare and analyze these seven annexin gene sequences and present the in situ RNA localization patterns of two of these genes, AnnAt1 and AnnAt2, during different stages of Arabidopsis development. Sequence analysis of AnnAt1--AnnAt7 reveals that they contain the characteristic four structural repeats including the more highly conserved 17-amino acid endonexin fold region found in vertebrate annexins. Alignment comparisons show that there are differences within the repeat regions that may have functional importance. To assess the relative level of expression in various tissues, reverse transcription-PCR was carried out using gene-specific primers for each of the Arabidopsis annexin genes. In addition, northern blot analysis using gene-specific probes indicates differences in AnnAt1 and AnnAt2 expression levels in different tissues. AnnAt1 is expressed in all tissues examined and is most abundant in stems, whereas AnnAt2 is expressed mainly in root tissue and to a lesser extent in stems and flowers. In situ RNA localization demonstrates that these two annexin genes display developmentally regulated tissue-specific and cell-specific expression patterns. These patterns are both distinct and overlapping. The developmental expression patterns for both annexins provide further support for the hypothesis that annexins are involved in the Golgi-mediated secretion of polysaccharides.

Non-NASA Center↗
NASA NTRS1978

Evaluation of compositional nonrandomness in proteins

The finite sampling component of Q, a measure of nonrandomness in the amino acid composition of proteins, is quantitatively estimated by using the natural abundances of amino acids rather than the genetic code table frequencies, and the revised value of Q implies that the value of Q(c), a measure of selective effects above and beyond those imposed by the average natural abundance of the amino acids, should be 9.7 rather than its previous value of 24.3. Individual Q(c) values are given for 81 protein families. The standard deviation of the population of Q(c) values is 12.5 but the Q(c) value differs significantly from the value of zero expected were the natural abundances of the amino acids the only selective constraint. The small value of Q(c) indicates that quantitatively minimal adjustments away from the average protein composition are necessary to maintain many different biological functions.

Holmquist, R.↗
NASA NTRS1998

Role of heat shock protein Hsp25 in the response of the orofacial nuclei motor system to physiological stress

Although expression of the small heat shock protein family member Hsp25 has been previously observed in the central nervous system (CNS), both constitutively and upon induction, its function in the CNS remains far from clear. In the present study we have characterized the spatial pattern of expression of Hsp25 in the normal adult mouse brain as well as the changes in expression patterns induced by subjecting mice to experimental hyperthermia or hypoxia. Immunohistochemical analysis revealed a surprisingly restricted pattern of constitutive expression of Hsp25 in the brain, limited to the facial, trigeminal, ambiguus, hypoglossal and vagal motor nuclei of the brainstem. After hyperthermia or hypoxia treatment, significant increases in the levels of Hsp25 were observed in these same areas and also in fibers of the facial and trigeminal nerve tracts. Immunoblot analysis of protein lysates from brainstem also showed the same pattern of induction of Hsp25. Surprisingly, no other area in the brain showed expression of Hsp25, in either control or stressed animals. The highly restricted expression of Hsp25 implies that this protein may have a specific physiological role in the orofacial motor nuclei, which govern precise coordination between muscles of mastication and the pharynx, larynx, and face. Its rapid induction after stress further suggests that Hsp25 may serve as a specific molecular chaperone in the lower cholinergic motor neurons and along their fibers under conditions of stress or injury. Copyright 1998 Elsevier Science B.V.

Non-NASA Center↗
NASA NTRS1981

Evolution of the rhodospirillaceae and mitochondria - A view based on sequence data

New sequence data from several protein families and from 5S ribosomal RNA confirm and elaborate a previously proposed description of the phylogenetic connections between a variety of bacteria and the eukaryotes. Probably, the first organisms were nonphotosynthetic anaerobic prokaryotes, which were followed soon by photosynthetic anaerobes. From this photosynthetic stock, the aerobic line to Pseudomonadacae, Rhodospirillaceae, and blue-greens arose. The eukaryotes derived genetic material from the symbioses of at least three separate bacterial lines. Ancestors of Rhodopseudomonas globiformis gave rise to the eukaryote mitochondria, probably through at least three separate symbioses, one early on the flagellate line, one on the ciliate line, and one on the stem to the multicellular forms.

Dayhoff, M. O.↗
NASA NTRS2005

Evaluation of Late Effects of Heavy-Ion Radiation on Mesenchymal Stem Cells

The overall objective of this recently funded study is to utilize well-characterized model test systems to assess the impact of pluripotent stem cell differentiation on biological effects associated with high-energy charged particle radiation. These stem cells, specifically mesenchymal stem cells (MSCs), have the potential for differentiation into bone, cartilage, fat, tendons, and other tissue types. The characterization of the regulation mechanisms of MSC differentiation to the osteoblastic lineage by transcription factors, such as Runx2/Cbfa1 and Osterix, and osteoinductive proteins such as members of the bone morphogenic protein family are well established. More importantly, for late biological effects, MSCs have been shown to contribute to tissue restructuring and repair after tissue injury. The complex regulation of and interactions between inflammation and repair determine the eventual outcome of the responses to tissue injury, for which MSCs play a crucial role. Additionally, MSCs have been shown to respond to reactive oxygen species, a secondary effector of radiation, by differentiating. With this, we hypothesized that differentiation of MSCs can alter or exacerbate the damage initiated by radiation, which can ultimately lead to late biological effects of misrepair/fibrosis which may ultimately lead to carcinogenesis. Currently, studies are underway to examine high-energy X-ray radiation at low and high doses, approximately 20 and 200 Rad, respectively, on cytogenetic damage and gene modulation of isolated MSCs. These cells, positive for MSC surface markers, were obtained from three persons. In vitro cell samples were harvested during cellular proliferation and after both cellular recovery and differentiation. Future work will use established in vitro models of increasing complexity to examine the value of traditional 2D tissue-culture techniques, and utilize 3D in vitro tissue culture techniques that can better assess late effects associated with radiation.

Gonda, S.R.↗
NASA NTRS2004

Purification and Crystallization of Murine Myostatin: A Negative Regulator of Muscle Mass

Myostatin (MSTN) has been crystallized and its preliminary X-ray diffraction data were collected. MSTN is a negative regulator of muscle growt/differentiation and suppressor of fat accumulation. It is a member of TGF-b family of proteins. Like other members of this family, the regulation of MSTN is critically tied to its process of maturation. This process involves the formation of a homodimer followed by two proteolytic steps. The first proteolytic cleavage produces a species where the n-terminal portion of the dimer is covalently separated from, but remains non-covalently bound to, the c-terminal, functional, portion of the protein. The protein is activated upon removal of the n-terminal "pro-segment" by a second n-terminal proteolytic cut by BMP-1 in vivo, or by acid treatment in vitro. Understanding the structural nature and physical interactions involved in these regulatory processes is the objective of our studies. Murine MSTN was purified from culture media of genetically engineered Chinese Hamster Ovary cells by multicolumn purification process and crystallized using the vapor diffusion method.

Hong, Young S.↗
NASA NTRS2019

Gravity as a Continuum: Effects of Altered Gravity on Drosophila Melanogaster Immunity

The impact of spaceflight on immune function is undoubtedly a critical focus in the area of space biology and human health research. Heat shock proteins (Hsp) are an evolutionarily conserved family of proteins that are expressed in response to cellular and physiological stressors, experienced during radiation exposure, confinement, circadian rhythm disruption, and altered gravity (hypergravity experienced at launch/landing and microgravity experienced in-flight). In particular, Hsp70 aids in the folding of proteins, facilitates the movement of proteins across the membranes during signal transductions and can stimulate innate immunity. Since Hsp70 is induced during cellular stress, and can act as a stimulator for innate immunity, we sought to address how a loss of Hsp70 affects immunity, under the stress-inducing model of acute and chronic hypergravity. Moreover, the effects of gravity as a continuum on the induction of Hsps and key immune genes were also assessed to determine if increased cellular stress, via increased gravity (g)-force, contributes to immune dysfunctions. For this, wildtype (W1118) and Hsp70 deficient (Hsp70null) Drosophila melanogaster were subjected to simulated hypergravity at increasing levels of g-force (1.2g, 3g, and 5g) for acute (1hr) and chronic (7-day) timepoints and were compared to 0g 'non-hypergravity' controls. Following simulation, whole bodies were sex-segregated, RNA was isolated and quantitative (q)PCR was performed to determine differential immune gene expression profiles. Further, functional output of hemocytes were assessed by a phagocytosis assay. Collectively, these studies evaluated the effects of Hsp70 in the context of immunity during acute and chronic hypergravity. Indeed, relevance for this work can directly translate to acute effects of launch/landing gravitational forces upon liftoff (~1.7g) and entry (~3.4g) that astronauts experience. In addition, the effects of chronic cellular stress is directly relevant to the immune health of astronauts on long duration missions, as well. Thus, as we approach the goal of returning to the Moon and landing the first humans on Mars, an evaluation of gravity as a continuum and the stress-inducing effects of altered gravity experienced during spaceflight on astronaut immunity and health are necessary.

Olivieri, Joe↗
NASA NTRS2002

Parathyroid hormone-dependent signaling pathways regulating genes in bone cells

Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific examples of this are still unknown. This review will focus on what is known about PTH-mediated cell signaling, and discuss the established or putative PTH-regulated pattern of gene expression in osteoblastic cells following treatment with catabolic (high) or anabolic (low) concentrations of the hormone.

NASA Discipline Musculoskeletal↗
NASA NTRS2021

Predicting the Functional State of Protein Kinases Using Interpretable Graph Neural Networks

Kinases are a family of proteins that function as molecular switches, regulating several essential cellular activities such as cell proliferation. Dysfunctional kinases are implicated in several types of cancers and hence they are actively pursued as drug targets. Given the vast number of complex kinase structures that are available in the protein data bank (PDB), there is a necessity to develop methodologies that can identify structurally important moieties of the kinases in an automated fashion, for such techniques can be instrumental in identifying novel drug targets. In this work, we develop a graph neural network (GNN) based deep learning framework for classifying the functionally active and inactive states of a large set of eukaryotic protein kinases, making use of their 3D structure from the PDB. We show that GNN based machine learning models can classify protein states with an accuracy greater than 97%. We further use the GNN models to automatically identify regions of the kinases that are important for its function. For this purpose, Gradient-weighted Class Activation Mapping (Grad-CAM) was implemented on the protein graphs. Remarkably, Grad-CAM consistently identifies the highly conserved DFG motif as the most important part of the protein across the entire kinome, without any prior input. Other regions of the hydrophobic core such as the HRD motif were also identified by the interpretable GNN framework, consistent with the literature. We discuss the significance of each of these regions in detail.

Ashwin Ravichandran↗