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PubMed2006

Characterizing the structures and folding of free proteins using 2-D gas-phase separations: observation of multiple unfolded conformers.

Understanding the 3-D structure and dynamics of proteins and other biological macromolecules in various environments is among the central challenges of chemistry. Electrospray ionization can often transfer ions from solution to gas phase with only limited structural distortion, allowing their profiling using mass spectrometry and other gas-phase approaches. Ion mobility spectrometry (IMS) can separate and characterize macroion conformations with high sensitivity and speed. However, IMS separation power is generally insufficient for full resolution of major structural variants of protein ions and elucidation of their interconversion dynamics. Here we report characterization of macromolecular conformations using field asymmetric waveform IMS (FAIMS) coupled to conventional IMS in conjunction with mass spectrometry. The collisional heating of ions in the electrodynamic funnel trap between FAIMS and IMS stages enables investigating the structural evolution of particular isomeric precursors as a function of the intensity and duration of activation that can be varied over large ranges. These new capabilities are demonstrated for ubiquitin and cytochrome c, two common model proteins for structure and folding studies. For nearly all charge states, two-dimensional FAIMS/IMS separations distinguish many more conformations than either FAIMS or IMS alone, including some with very low abundance. For cytochrome c in high charge states, we find several abundant "unfolded" isomer series not distinguishable by IMS, possibly corresponding to different "string of beads" geometries. The unfolding of specific ubiquitin conformers selected by FAIMS has been studied by employing their heating in the FAIMS/IMS interface.

Cytochromes c↗
PubMed1993

[Fibrinogen, a vascular risk factor].

Epidemiological studies have consistently correlated plasma fibrinogen level to the risk of coronary heart disease (CHD) and acute ischemic stroke. Several mechanisms have been proposed such as the role of fibrinogen in the viscosity of blood, the participation of fibrinogen in both fibrin clot formation and platelet aggregation. However, there is no evidence that the increase in fibrinogen is directly responsible for the vascular disease since the cytokines which participate to the synthesis of fibrinogen by the hepatocytes, such as interleukin 6, could also induce an endothelial cell damage by increasing tumor necrotic factor (TNF) production. In these conditions fibrinogen increase could therefore only represent a marker of cytokine production which in turn is responsible for vascular injury. In addition, for the pathogenesis of atherosclerosis, the influence of fibrinogen is not only mediated by way of increased fibrinogen concentration but could be due to a structurally variant fibrinogen. The recent epidemiological studies have shown that the variation at the beta locus of fibrinogen is associated with an increase risk of peripheral atherosclerosis. The finding concerning dysfibrinogenemia and thrombosis (Dusart and Tampere) create further opportunities to enrich knowledge of the link between the association of abnormal gel structure and thrombotic diseases such as myocardial infarction or stroke at young age. This abnormal clot structure could contribute to thrombogenicity by decreasing the capacity of these clots to be degraded by fibrinolytic enzymes or by decreasing thrombin binding since fibrin is considered as a "thrombin trap".(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinogen↗
PubMed1997

Variation of microcystins, cyanobacterial hepatotoxins, in Anabaena spp. as a function of growth stimuli.

Cyanobacterial hepatotoxins, microcystins, are specific inhibitors of serine/threonine protein phosphatases and potent tumor promoters. They have caused several poisonings of animals and also pose a health hazard for humans through the use of water for drinking and recreation. Different strains of the same cyanobacterial species may variously be nontoxic, be neurotoxic, or produce several microcystin variants. It is poorly understood how the amount of toxins varies in a single strain. This laboratory study shows the importance of external growth stimuli in regulating the levels and relative proportions of different microcystin variants in two strains of filamentous, nitrogen-fixing Anabaena spp. The concentration of the toxins in the cells increased with phosphorus. High temperatures (25 to 30 degrees C), together with the highest levels of light studied (test range, 2 to 100 mumol m-2 s-1), decreased their amount. Different structural variants of microcystins responded differently to growth stimuli. Variants of microcystin (MCYST)-LR correlated with temperatures below 25 degrees C, and those of MCYST-RR correlated with higher temperatures. Nitrogen added into the growth medium and increasing temperatures increased the proportion of microcystin variants demethylated in amino acid 3. All variants remained mostly intracellular. Time was the most important factor causing the release of the toxins into the growth medium. Time, nitrogen added into the growth medium, and light fluxes above 25 mumol m-2 s-1 significantly increased the concentrations of the dissolved toxins. According to the results, it thus seems that the reduction of phosphorus loads in bodies of water might play a role in preventing the health hazards that toxic cyanobacterial water blooms pose, not only by decreasing the cyanobacteria but also by decreasing their toxin content.

Anabaena↗
PubMed2026

Diverse mediators of cancer predisposition uncovered by germline whole genome sequencing of unexplained familial cancers.

Cancer frequently clusters in families due to shared environment and genetics. However, many familial cancer cases lack a clinically recognized pathogenic germline variant (PGV). We analyzed germline genomes and family history from 2,726 individuals without a PGV in the All of Us Research Program, including 1,496 cases across 18 cancer types with extensive family history and 1,230 family history-negative, cancer-free controls. We identified allelic series of rare structural variants inactivating MSH2 in individuals with phenotypes consistent with Lynch syndrome and BRCA1 in breast cancer. Cancer polygenic risk scores were enriched in cases and correlated with patterns of cancer diagnoses within families. Exome-wide rare variant analyses nominated six candidate predisposition genes, including TSTD2 and BRAT1 in thyroid and breast cancer, respectively. Overall, polygenic risk and rare variants impacting known genes explained a median of 5% of unexplained familial cancers, increasing to 11% when including newly nominated risk factors.

Journal Article↗
PubMed2005

Parallel, solution phase synthesis of dihydropyridine miticides via a versatile multicomponent reaction.

A novel class of highly active dihydropyridine miticides was prepared using a multicomponent reaction process. The initial lead was rapidly optimized using solution phase parallel synthesis techniques and a positional scanning approach. Detailed structure-activity relationships were developed for the amino and carbonyl components of the molecule and used to select the best candidates for broad field testing. The chemistry, biology and toxicology of these compounds will be presented along with numerous structural variants of the reaction products.

Agrochemicals↗
PubMed2026

ONT-only genome assembly of a Korean male individual using a semen sample.

BACKGROUND: Long-read sequencing has enabled the generation of high-quality human genome assemblies, but many previous assemblies were based on blood-derived DNA and often relied on limited data types from a single sequencing strategy. OBJECTIVE: This study aimed to generate high-quality phased genome assemblies of a Korean individual using multiple independent long-read datasets produced from a single sequencing platform and to evaluate their utility for chromosome-scale assembly and variant detection. METHODS: Genomic DNA was extracted from a semen sample of a Korean male. Long-read, ultra-long-read, and chromatin conformation capture sequencing data were generated using Oxford Nanopore Technologies. These datasets were integrated to construct phased genome assemblies, followed by correction of noticeable phasing errors and assessment of assembly continuity, chromosomal representation, telomeric repeat recovery, and variant detection performance. RESULTS: The final phased assemblies spanned approximately 2.9 Gb and represented 23 pairs of chromosomes with an NG50 of 150 Mb. Telomeric repeats were detected at 36 and 37 of the 48 chromosomal ends in the two assemblies, indicating high end-to-end completeness. In addition, we successfully identified structural variants, including small variants. These results demonstrate that combining multiple Oxford Nanopore data types can produce highly continuous and informative phased human genome assemblies. CONCLUSIONS: We generated high-quality phased genome assemblies of a Korean individual using Oxford Nanopore long-read sequencing data derived from semen DNA. This publicly available genome resource will support broader applications of long-read sequencing in human genomics and variant analysis.

Humans↗
PubMed1984

Staphylococcal enterotoxin A gene is associated with a variable genetic element.

The genetic determinant of Staphylococcus aureus enterotoxin A (SEA) has been cloned in pBR322 in Escherichia coli and found to be expressed and secreted into the periplasmic space in that organism. The SEA gene (entA) is within a 2.5-kilobase-pair HindIII fragment that is part of a discrete genetic element 8-12 kilobase pairs in length. This entA element has a standard chromosomal location [between the purine (pur) and isoleucine-valine (ilv) markers] in most S. aureus strains. In some strains it is unlinked to pur-ilv. However, its internal structure is conserved at different locations. Some naturally occurring SEA-nonproducer (EntA-) strains lack the entire entA element, and one instance of its spontaneous loss is reported. Other naturally occurring strains have EntA- structural variants of the element at the same pur-ilv location at which the intact element is most commonly found. Some of these strains are EntA-, others are EntA+; the latter have a second, unlinked copy of the element containing their functional entA gene. These results suggest that entA is associated with a structurally unstable, possibly mobile, discrete genetic element.

DNA Restriction Enzymes↗
PubMed1986

Variation in alpha-L-fucosidase properties among 28 inbred mouse strains: six strains have high enzyme activity and heat-stabile enzyme with a variant pH-activity curve; twenty-two strains have low activity and heat-labile enzyme.

Alpha-L-fucosidase in tissues of 28 inbred mouse strains varied with respect to three properties: high or low heat stability, a pH-activity curve with high or low relative activity at pH 2.8, and high or low activity. Alpha-L-fucosidase from six strains (A/J, BDP/J, LP/J, P/J, SEA/GNJ, and 129/J) had high heat stability, high pH 2.8 relative activity, and high activity, whereas the other 22 strains all had low heat stability, low pH 2.8 relative activity, and low activity. The heat-stability difference was seen in all organs tested (brain, liver, kidney, spleen, heart, skeletal muscle, lung, and testis) for two heat-stabile strains (P/J and 129/J) and four heat-labile strains (C57BL/6J, C3H/HeJ, DBA/2J, and BALB/cJ) studied in detail. The findings suggested that two structural variants of alpha-L-fucosidase, probably genetically determined, exist in these 28 inbred mouse strains, although the presence of linkage disequilibrium between alleles of tightly linked structural and regulatory genes could not be excluded.

Animals↗
PubMed2026

Germline determinants of risk and molecular subtype in young-onset lung cancer.

Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02x10-7) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39x10-6) and SMAD6 in fusion-negative tumors (p=2.05x10-6). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8x10-5) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.

Journal Article↗
PubMed2003

Identification and characterization of the reptilian GnRH-II gene in the leopard gecko, Eublepharis macularius, and its evolutionary considerations.

To elucidate the molecular phylogeny and evolution of a particular peptide, one must analyze not the limited primary amino acid sequences of the low molecular weight mature polypeptide, but rather the sequences of the corresponding precursors from various species. Of all the structural variants of gonadotropin-releasing hormone (GnRH), GnRH-II (chicken GnRH-II, or cGnRH-II) is remarkably conserved without any sequence substitutions among vertebrates, but its precursor sequences vary considerably. We have identified and characterized the full-length complementary DNA (cDNA) encoding the GnRH-II precursor and determined its genomic structure, consisting of four exons and three introns, in a reptilian species, the leopard gecko Eublepharis macularius. This is the first report about the GnRH-II precursor cDNA/gene from reptiles. The deduced leopard gecko prepro-GnRH-II polypeptide had the highest identities with the corresponding polypeptides of amphibians. The GnRH-II precursor mRNA was detected in more than half of the tissues and organs examined. This widespread expression is consistent with the previous findings in several species, though the roles of GnRH outside the hypothalamus-pituitary-gonadal axis remain largely unknown. Molecular phylogenetic analysis combined with sequence comparison showed that the leopard gecko is more similar to fishes and amphibians than to eutherian mammals with respect to the GnRH-II precursor sequence. These results strongly suggest that the divergence of the GnRH-II precursor sequences seen in eutherian mammals may have occurred along with amniote evolution.

Amino Acid Sequence↗
PubMed1979

Structure-activity relationships among daunorubicin and adriamycin analogs.

Structural characteristics of Adriamycin and daunorubicin analogs are discussed in terms of three antitumor activity classifications: compounds with potency and efficacy equivalent to or superior to the parent antibiotics, compounds displaying high efficacy but with decreased potency, and compounds in which a key structural change has destroyed all in vivo antitumor activity. It is first concluded that analogs possessing efficacy and potency comparable to the parent antibiotics are quite similar to the parents in structural terms, ie, their hydrophilic character, functional groups, and stereochemistry. Within this group there is suggestive evidence that altered electronic character of the aglycones may be associated with improved cardiotoxicity characteristics. The second general conclusion is that high efficacy accompanied by decreased potency is compatible with a much wider array of structural variants than is high efficacy accompanied by high potency. Thus, analogs with substantially higher or lower lipophilicity than the parent antibiotics, as well as those with an array of ionic characteristics differing from the parents, retained significant efficacy. These characteristics are compatible with the concept of multiple mechanisms of action for the anthracycline antibiotics. In general, structural changes in the sugar side chain are appreciably more compatible with retention of in vivo antitumor efficacy than are changes in the aglycone, both in terms of functional groups and stereochemistry.

Animals↗
PubMed1992

Molecular basis for the human erythrocyte glycophorin specifying the Miltenberger class I (MiI) phenotype.

Human glycophorin Mil (HGpMil) is a structural variant of the MNSs blood group system that specifies the Miltenberger class I phenotype. We report here the molecular basis of the HGpMil gene identified in a white family in which the first homozygote was encountered. Immunoblotting analysis showed the expression of HGpMil and HGpB but the absence of HGpA on the homozygous Mil erythrocytes. Southern blot analysis detected no gross alterations in gene structure or band intensity. Genomic sequences encompassing exons II and III of the HGpMil gene were amplified by single-copy polymerase chain reaction. Restriction digestion and direct DNA sequence analysis showed that HGpMil gene is derived from an alpha N allele of HGpA and differs from the latter in the third exon by a single nucleotide change. In HGpMil, the presence of a deoxythymidine at the second position of codon 28 (ATG) not only resulted in a methionine substitution but also altered the consensus sequence for N-glycosylation from Asn-Asp-Thr to Asn-Asp-Met. These data are consistent with the occurrence of Mil on the red blood cell membrane as a variant deficient in the asparagine-linked carbohydrate unit. Significantly, this particular point mutation lies in between the two half-sites of a direct repeat that has been implicated to facilitate the recombination events leading to several other glycophorin genes of the Miltenberger series. Based on this relatedness, we propose an untemplated nucleotide replacement resulting from a gene conversion event as the molecular basis for the origin of HGpMil gene.

Amino Acid Sequence↗
PubMed1980

[Histogenesis of stomach cancer].

A conclusion on histogenetic unity of various structural variants of carcinoma of the stomach is drawn from the analysis of the data from literature and the own observations referring to light and electron microscopy and histochemistry of precancer alterations of the gastric mucosa and carcinoma of the stomach as well as the clinical pattern and prognosis of carcinoma of the stomach depending on the morphological structure of the tumour. All the variety of morphological and functional properties of tumours depends on the level and direction of differentiation of carcinoma cells.

Adenocarcinoma↗
PubMed2005

CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes.

OBJECTIVE: The goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations between CYP2C9 haplotypes and anticoagulation-related outcomes. METHODS: Genomic deoxyribonucleic acid from 192 European American patients stabilized on warfarin therapy was resequenced across 60 kilobases of the CYP2C9 genomic region, including all exons, dense sampling of introns, approximately 10 kilobases of the 5'-flanking region, and approximately 1.7 kilobases of the 3'-untranslated region. RESULTS: A total of 132 single nucleotide polymorphisms (SNPs) were detected, of which 47 were present in the 5'-flanking promoter region, 11 in the exonic coding region, and 74 in the intron regions. Nine nonsynonymous SNPs in the coding region consisted of CYP2C9*2 , *3 , *9 , *11 , and *12 ; R125H; and 3 new structural variants. Sixty SNPs were present at a minor allele frequency of greater than 5%, and from this subpopulation, 23 haplotypes were inferred. Clustering analysis identified 6 major groups of related haplotypes that were further designated 1A, 1B, 1C, 1D, 2, or 3. The *2 and *3 SNPs appeared exclusively in groups 2 and 3, and these groups combined were associated with significantly reduced warfarin maintenance doses, longer time to stable dosing, and increased risk of bleeding. In contrast, combinations of haplotypes 1A, 1B, 1C, and 1D were not associated with differences in any of these outcomes. CONCLUSION: These data establish a whole-gene, high-resolution haplotype structure for CYP2C9 in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for warfarin sensitivity associated with CYP2C9 variants in this population.

Alleles↗
PubMed1983

A new glucose 6-phosphate dehydrogenase variant (G-6-PD Verona) in a patient with myelodysplastic syndrome.

A 67-year-old woman investigated because of 'myelodysplastic syndrome' was found to have a 4-fold increase in G-6-PD activity in her erythrocytes. The enzyme was partially purified and characterized. On grounds of: (a) reduced electrophoretic mobility, (b) abnormal cathodic band(s) in isoelectrofocusing, (c) increased Michaelis constant for glucose 6-phosphate, (d) abnormal thermostability, and (e) abnormal interaction with the ligand NADPH, we conclude that this is a new structural variant which we designate G-6-PD Verona. G-6-PD Verona was the sole apparent source of G-6-PD activity in the patient's erythrocytes; by contrast, the patient's fibroblasts had only normal G-6-PH (type B). The patient's haematological course terminated into acute myeloid leukaemia. We believe G-6-PD Verona was the result of a somatic mutation in an X-chromosome which took place in a haemopoietic cell clone which subsequently underwent neoplastic transformation.

Aged↗
PubMed2002

Adjuvant activity of emulsan, a secreted lipopolysaccharide from acinetobacter calcoaceticus.

Several promising adjuvant candidates have been studied over the past 75 years; however, only alum is currently approved for human use. The complex acylated polysaccharide emulsan, secreted from Acinetobacter calcoaceticus, represents a new candidate. Unique features of this family of polymers are their amenability to structural tailoring and their emulsification behavior. We demonstrate that emulsan activates macrophages in a dose-dependent manner. This activation is dependent on the presence of the fatty acid side chains that decorate the polysaccharide backbone, and, furthermore, the level of activation can be affected by changes in the chemical characteristics of emulsan structural variants. One emulsan variant was examined in a classical hapten carrier immunization protocol and demonstrated significant adjuvant activity as determined by hapten-specific antibody titers. This immune response was characterized by a high immunoglobulin G2a titer, consistent with a Th1 response. The significant immunopotentiation demonstrated by this complex polymer establishes emulsan as an exciting new candidate adjuvant. Furthermore, by manipulating the chemical structure of this compound, we can explore the physical basis of pattern recognition receptors and macrophage activation.

Adjuvants, Immunologic↗
PubMed1996

Modeling of the D1/D2 proteins and cofactors of the photosystem II reaction center: implications for herbicide and bicarbonate binding.

A three-dimensional model of the photosystem II (PSII) reaction center from the cyanobacterium Synechocystis sp. PCC 6803 was generated based on homology with the anoxygenic purple bacterial photosynthetic reaction centers of Rhodobacter sphaeroides and Rhodopseudomonas viridis, for which the X-ray crystallographic structures are available. The model was constructed with an alignment of D1 and D2 sequences with the L and M subunits of the bacterial reaction center, respectively, and by using as a scaffold the structurally conserved regions (SCRs) from bacterial templates. The structurally variant regions were built using a novel sequence-specific approach of searching for the best-matched protein segments in the Protein Data Bank with the "basic local alignment search tool" (Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ, 1990, J Mol Biol 215:403-410), and imposing the matching conformational preference on the corresponding D1 and D2 regions. The structure thus obtained was refined by energy minimization. The modeled D1 and D2 proteins contain five transmembrane alpha-helices each, with cofactors (4 chlorophylls, 2 pheophytins, 2 plastoquinones, and a non-heme iron) essential for PSII primary photochemistry embedded in them. A beta-carotene, considered important for PSII photoprotection, was also included in the model. Four different possible conformations of the primary electron donor P680 chlorophylls were proposed, one based on the homology with the bacterial template and the other three on existing experimental suggestions in literature. The P680 conformation based on homology was preferred because it has the lowest energy. Redox active tyrosine residues important for P680+ reduction as well as residues important for PSII cofactor binding were analyzed. Residues involved in interprotein interactions in the model were also identified. Herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) was also modeled in the plastoquinone QB binding niche using the structural information available from a DCMU-binding bacterial reaction center. A bicarbonate anion, known to play a role in PSII, but not in anoxygenic photosynthetic bacteria, was modeled in the non-heme iron site, providing a bidentate ligand to the iron. By modifying the previous hypothesis of Blubaugh and Govindjee (1988, Photosyn Res 19:85-128), we modeled a second bicarbonate and a water molecule in the QB site and we proposed a hypothesis to explain the mechanism of QB protonation mediated by bicarbonate and water. The bicarbonate, stabilized by D1-R257, donates a proton to QB2- through the intermediate of D1-H252; and a water molecule donates another proton to QB2-. Based on the discovery of a "water transport channel" in the bacterial reaction center, an analogous channel for transporting water and bicarbonate is proposed in our PSII model. The putative channel appears to be primarily positively charged near QB and the non-heme iron, in contrast to the polarity distribution in the bacterial water transport channel. The constructed model has been found to be consistent with most existing data.

Amino Acid Sequence↗
PubMed1987

Distribution of HLA-B27 subtypes in patients with ankylosing spondylitis: the disease is associated with a common determinant of the various B27 molecules.

HLA-B27 subtypes can be defined by cellular, serological, and biochemical techniques. The seven subtypes so far identified represent structural variants of B27 with limited variations in the amino acid sequence of the B27 molecule. The routinely typed B27 'antigen' remains a common (shared, public) determinant present on various B27 molecules. The distribution of the subtypes varies strongly among different ethnic groups and they occur in different linkage disequilibria. In the healthy Dutch population only two subtypes were found: B27W (B27 X 1, B27M2+) (90%) and B27K (B27 X 2, B27M2-) (10%). A similar distribution of B27 subtypes was observed in 91 unrelated Dutch patients with ankylosing spondylitis (AS)--namely, 92% B27W and 8% B27K. In Oriental populations the subtype distribution is quite different: B27W occurs in less than 50%, whereas more than 50% individuals are of the B27C and B27D subtypes. Preliminary data indicate that the distribution of subtypes in healthy and diseased Oriental individuals is similar. These results suggest that the B27 and disease (AS) association is not correlated with the structural variations of one of the B27 subtypes, but with a common B27 determinant shared by various B27 subtypes. Consequently, the disease is older than the B27 variants. Further studies on disease and subtype distribution in various ethnic groups might contribute to a better understanding of the origin of both.

Asian People↗