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Results for “molecular functions”

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PubMed2001

Functional, molecular, and biochemical characterization of streptozotocin-induced diabetes.

Altered divalent cation homeostasis with bone mineral loss, hypercalciuria, and hypomagnesemia have been associated consistently with human diabetes mellitus. This study investigated functional, molecular, and biochemical determinants that accompany this condition in chronically (2 wk) streptozotocin (STZ)-diabetic rats. Catheterized, conscious, diabetic rats on servo-controlled fluid replacement exhibited an increased GFR (+70%) and a substantially raised urinary calcium output (+568%) when compared with control rats. In addition, fractional calcium reabsorption was reduced, indicating that the hypercalciuria was not due solely to an osmotic effect but may involve an actual tubular defect. The expression of proteins involved in renal distal Ca2+ and water transport in STZ-diabetic rats were then studied by Western analysis and immunofluorescence microscopy to investigate the molecular basis of the hypercalciuria. Extracellular Ca2+-sensing receptor abundance was reduced to 52% of control in STZ-diabetes, whereas thiazide-sensitive NaCl cotransporter expression was increased by 192%. Subcutaneous insulin implant rectified both functional and molecular parameters. The levels of calbindin D(28k), plasma membrane Ca2+ ATPase, and aquaporin 1 in whole kidney and of aquaporin 2 in inner medulla were unchanged in diabetic and/or insulin replacement. Blood levels of 1,25(OH)(2)D(3) were reduced in diabetes as were levels of osteocalcin, a marker of bone formation. It is concluded that diabetic hypercalciuria in rats involves elevated GFR with raised urinary output, reduced Ca2+ reabsorption, and impaired bone deposition. Changes in Ca2+-sensing receptor and NaCl cotransporter protein expression could account for the altered divalent cation homeostasis seen during diabetes mellitus.

Animals↗

PubMed2005

Go molecular function terms are predictive of subcellular localization.

A protein's function is closely linked to its subcellular localization. Use of Gene Ontology (GO) molecular function terms to extend sequence-based subcellular localization prediction has been previously shown to improve predictive performance. Here, we explore directly the relationship between GO function annotations and localization information, identifying both highly predictive single terms, and terms with large information gain with respect to location. The results identify a number of predictive and informative GO terms with respect to subcellular location, particularly nucleus, extracellular space, membrane, mitochondrion, endoplasmic reticulum and Golgi. There are several clear examples illustrating why the addition of function information provides additional predictive power over sequence alone. Other interesting phenomena can also be seen in the results. Most predictive or informative terms are imperfect, and incorrect prediction may often call out significant biological phenomena. Finally, these results may be useful in the GO annotation process.

Amino Acid Sequence↗

PubMed2003

Adaptation at specific loci. VII. Natural selection, dispersal and the diversity of molecular-functional variation patterns among butterfly species complexes (Colias: Lepidoptera, Pieridae).

Natural genetic variants at the phosphoglucose isomerase, PGI, gene differ in spatial patterning of their polymorphism among species complexes of Colias butterflies in North America. In both lowland and alpine complexes, molecular-functional properties of the polymorphic genotypes can be used to predict genotype-specific adult flight performances and resulting large genotypic differences in adult fitness components. In the lowland species complex, there is striking uniformity of PGI polymorph frequencies at a number of sites across the American West; this fits with earlier findings of strong, similar differences in fitness components over this range. In an alpine complex, Colias meadii shows similar uniformity of PGI frequencies within habitat types, either montane steppe or alpine tundra, over several hundred kilometres in the absence of dispersal. At the same time, large shifts (10-20%) in frequency of the most common alleles occur between steppe and tundra populations, whether these are isolated or, as in some cases, are in contact and exchange many dispersing adults each generation. Data on male mating success of common C. meadii PGI genotypes in steppe and tundra show heterozygote advantage in both habitat types, with shifts in relative homozygote disadvantage between habitats which are consistent with observed frequency differences. Nonadaptive explanations for this situation are rejected, and alternative, thermal-ecology-based adaptive hypotheses are proposed for later experimental test. These findings show that strong local selection may dominate dispersal as an evolutionary agent, whether or not dispersal is present, and that selection may often be the major force promoting 'cohesion' of species over long distances. This case offers new opportunities for integrating studies of molecular structure and function with ecological aspects of natural selection in the wild, both within and among species.

Adaptation, Biological↗

PubMed1992

Functional molecular mass of the 14C-azidobenzamidotaurocholic acid binding proteins in hepatocellular bile acid transport systems.

The apparent target size of 14C-azidobenzamidotaurocholate binding proteins in basolateral rat liver plasma membranes (blPm) was determined by analysis of the radiation induced decrease of the binding of this photoreactive taurocholate analog to blPm. Radiation causes a dose-dependent mono-exponential reduction of binding of ABATC to the protein subunits with molecular masses of 48-50 and 52-54 kDa in SDS-PAGE. The minimal functional molecular mass of the 48-50 and 52-54 kDa ABATC binding proteins was determined to be 99 +/- 8.2 and 93.2 +/- 7 kDa, respectively.

Animals↗

PubMed2006

Neurotransmitter transporters: molecular function of important drug targets.

The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and/or glial cells: the solute carrier (SLC)1 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of glutamate, and the SLC6 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of dopamine, 5-HT, norepinephrine, glycine and GABA. Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters to be generated. These models should be an important tool for developing specific drugs that, through selective interaction with transporters, could improve the treatment of serious neurological and psychiatric disorders.

Animals↗

PubMed2005

The blood-brain barrier sodium-dependent multivitamin transporter: a molecular functional in vitro-in situ correlation.

The molecular mechanism of biotin brain uptake was investigated using an in vitro bovine blood-brain barrier (BBB) cell model and an in situ mouse brain perfusion technique. A functional uptake/transport correlation of the in vitro and in situ characteristics of biotin uptake was investigated. Morphological and immunochemical characteristics (e.g., factor VIII expression) of the primary culture of brain microvessel endothelial cells (BMECs) were confirmed. Gene expression of the multidrug resistance (Mdr1) and sodium-dependent multivitamin (SMVT) transporters was also determined in BMECs. Biotin transport was saturable and Na(+)-dependent at the luminal side of the BBB. The estimated half-saturation concentrations (K(m)) of biotin uptake in vitro and in situ were 49.1 and 35.5 microM, respectively, supporting the presence of a carrier-mediated biotin transport system. Inhibition studies using various biotin derivatives and structural analogs demonstrated the structural requirements for biotin-SMVT interaction. Desthiobiotin and pantothenic acid significantly inhibited the uptake of biotin, whereas 2-iminobiotin and diaminobiotin were very weak inhibitors. Based on our results, there was a good correlation between the in vitro and in situ BBB models, suggesting that when a single membrane transporter is involved in substrate uptake, flexibility in choosing the experimental model can be afforded. The current results are also consistent with the suggestion that the properties of the BBB are likely to be organ-specific rather than species-specific. Further mechanistic and comparative studies are needed to validate these results. In conclusion, the in vitro transporter-based mechanism studies produced valuable molecular functional transport results that correlated well with in situ results.

Animals↗

PubMed1986

Characteristics of ethacrynic acid highly sensitive Mg2+-ATPase in microsomal fractions of the rat brain: functional molecular size, inhibition by SITS and stimulation by Cl-.

Studies were performed to characterize ethacrynic acid (EA) highly sensitive Mg2+-ATPase isolated from microsomal fractions of the rat brain. The functional molecular sizes of the EA highly sensitive and EA less sensitive Mg2+-ATPases, estimated by a radiation inactivation method, were 480 and 80 kDa, respectively. An anion transport inhibitor, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) inhibited the EA highly sensitive Mg2+-ATPase activity. The type of inhibition was uncompetitive with respect to ATP, and the inhibition was suppressed by anions such as Cl-, Br- and I-. Chloride ions stimulated enzyme activity with an increase in Vmax, but not in Km, for ATP. Anions tested also increased the enzyme activity in the following order of decreasing potency: Cl- greater than Br- greater than CH3COO- = I- greater than SO4(2-) = HCO3- greater than SO3(2-). These results suggest that EA highly sensitive Mg2+-ATPase is a relatively large molecule with anion-sensitive sites that affect the ATP hydrolyzing activity and the SITS binding capacity through anions, with Cl- being the most potent.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed2002

Crystal structure of MJ1247 protein from M. jannaschii at 2.0 A resolution infers a molecular function of 3-hexulose-6-phosphate isomerase.

The crystal structure of the hypothetical protein MJ1247 from Methanococccus jannaschii at 2 A resolution, a detailed sequence analysis, and biochemical assays infer its molecular function to be 3-hexulose-6-phosphate isomerase (PHI). In the dissimilatory ribulose monophosphate (RuMP) cycle, ribulose-5-phosphate is coupled to formaldehyde by the 3-hexulose-6-phosphate synthase (HPS), yielding hexulose-6-phosphate, which is then isomerized to fructose-6-phosphate by the enzyme 3-hexulose-6-phosphate isomerase. MJ1247 is an alpha/beta structure consisting of a five-stranded parallel beta sheet flanked on both sides by alpha helices, forming a three-layered alpha-beta-alpha sandwich. The fold represents the nucleotide binding motif of a flavodoxin type. MJ1247 is a tetramer in the crystal and in solution and each monomer has a folding similar to the isomerase domain of glucosamine-6-phosphate synthase (GlmS).

Amino Acid Sequence↗

PubMed2026

Translating functional molecular knowledge into crop-breeding success.

Historical plant breeding, which optimizes phenotypes through selective crossing guided by phenotypic evaluation and molecular markers, is limited by evolutionary constraints that hinder rapid crop improvement. A new paradigm, precision breeding, circumvents these limitations by targeting genetic variants through functional molecular knowledge. To generate this knowledge at scale, sequence-based deep learning leverages high-quality genome sequence data to predict variant effects at base-pair resolution. When linked to agronomically important traits, these predictions enable breeders to prioritize variants for precision selection or editing. Although it is still in the early stages of development, we foresee three key applications for this approach: introgressing genes from distant breeding pools, purging deleterious mutations and designing new plant ideotypes. Looking ahead, refined computational models will facilitate targeted editing and the systematic redesign of complex physiological processes to address emerging breeding goals under shifting environmental conditions.

Crops, Agricultural↗

PubMed2004

Intraocular implantation of DNA-transfected retinal pigment epithelium cells: a new approach for analyzing molecular functions in the newt retinal regeneration.

Adult newts can regenerate their entire retinas, even after surgical removal of the neural retina (retinectomy), through transdifferentiation of the retinal pigment epithelium (RPE) cells. To develop a new experimental system for analyzing molecular functions during retinal regeneration of adult newts, we attempted to deliver a foreign gene into RPE cells of retina-less eye-cups in vitro. Here we used pCS2mt-GFP as a reporter construct, and selected Polyfect as a transfection reagent. DNA-transfection appeared to be restricted to the RPE cells of retina-less eye-cups and its efficiency was 0.1-0.2%. We tried to implant RPE-choroid tissue containing DNA-transfected RPE cells into the eye of a host animal. The tissue was placed into the posterior eye-chamber immediately after retinectomy so that the implanted RPE tissue was facing the cornea (i.e., normal orientation). The implant and host RPE regenerated one continuous hybrid neural retina. Ocular sections after 60 days of implantation showed that a small number of cells in the regenerating retina were intensely stained with an anti-GFP antibody. Some of those cells were believed to be retinal cells such as ganglion cells, amacrine cells and photoreceptors. The GFP-positive cells in the hybrid regenerating retina could represent clones derived from a single RPE cell. These results indicate that this experimental system could become useful in the study of adult newt retinal regeneration.

Animals↗

PubMed2006

IgA-CD89 complex in IgA nephropathy: a study on molecular function.

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. The basic pathogenesis of this disease is believed to be due to the complex formation between Fc IgA, alphaRI (CD89), and transferrin receptor (CD71), leading to the damage of the glomerulus. However, studying the functional aberration in the human IgA, CD89, and CD71 complex formation in pathogenesis of IgA nephropathy is hard. Here, the author used a new gene ontology technology to predict the molecular function of human IgA, CD89, and CD71 complex. It can be seen that the two main functional aberrations of IgA-CD89 complex might be due to signal transduction and binding activity.

Antigen-Antibody Complex↗

PubMed2005

An update on the functional molecular immunology (FIMM) database.

Data on the major histocompatibility complex, T-cell epitopes, B-cell epitopes, antigens and diseases are heterogeneous and scattered among different databases and the literature. Since it has become increasingly difficult to obtain an integrated view of functional immune response components, we have developed and updated over several years the Functional molecular IMMunology (FIMM) database (http:// research.i2r.a-star.edu.sg/fimm/). FIMM contains integrated expert-curated data on protein antigens, and on human immunological receptors that recognise and bind them in healthy or disease states. Interfaces with multiple, intuitive query options and query reports provide immunologists with prioritised information that aids data interpretation, vaccine target discovery and immune disease research.

Allergy and Immunology↗

PubMed2006

Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.

The peripheral-type benzodiazepine receptor or recognition site (PBR) is a widely distributed transmembrane protein that is located mainly in the outer mitochondrial membrane. The PBR binds to high-affinity drug ligands and cholesterol. Many functions are associated directly or indirectly with the PBR, including the regulation of cholesterol transport and the synthesis of steroid hormones, porphyrin transport and heme synthesis, apoptosis, cell proliferation, anion transport, regulation of mitochondrial functions and immunomodulation. Based on these functions, there are many potential clinical applications of PBR modulation, such as in oncologic, endocrine, neuropsychiatric and neurodegenerative diseases. Although "PBR" is a widely used and accepted name in the scientific community, recent data regarding the structure and molecular function of this protein increasingly support renaming it to represent more accurately its subcellular role (or roles) and putative tissue-specific function (or functions). Translocator protein (18kDa) is proposed as a new name, regardless of the subcellular localization of the protein.

Animals↗

PubMed2006

Molecular functions and biological roles of hepatitis B virus x protein.

Chronic infection of hepatitis B virus (HBV) is one of the major causes of hepatocellular carcinoma (HCC) in the world. Hepatitis B virus X protein (HBx) has been long suspected to be involved in hepatocarcinogenesis, although its oncogenic role remains controversial. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progress, protein degradation pathways, apoptosis, and genetic stability by directly or indirectly interacting with host factors. This review focuses on the biological roles of HBx in HBV replication and cellular transformation in terms of the molecular functions of HBx. Using the transient HBV replication assay, ectopically expressed HBx could stimulate HBV transcription and replication with the X-defective replicon to the level of those with the wild one. The transcription coactivation is mainly contributing to the stimulatory role of HBx on HBV replication although the other functions may affect HBV replication. Effect of HBx on cellular transformation remains controversial and was never addressed with human primary or immortal cells. Using the human immortalized primary cells, HBx was found to retain the ability to overcome active oncogene RAS-induced senescence that requires full-length HBx. At least two functions of HBx, the coactivation function and the ability to overcome oncogene-induced senescence, may be cooperatively involved in HBV-related hepatocarcinogenesis.

Amino Acid Sequence↗

PubMed2003

Shape-persistency and molecular function in heteromacrocycles: creation of heteroarenecyclynes and arene-azaarenecyclynes.

On the basis of our concept that the introduction of heteroatoms and shape-persistency into the pi-macrocycles should bring forth striking functions or properties, heteroarenecyclynes (such as oxaarenecyclynes and thiaarenecyclynes) with semi-shape-persistent structure, and arene-azaarenecyclynes with shape-persistent structure have been prepared. Their novel functions and characteristic properties are disclosed. Noteworthy is that heteroarenecyclynes include C(60) to provide a Saturn-type complex with a N(2) binding function. A simple member of the oxaarenecyclyne compounds undergoes the Ag(I)-induced cyclization leading to the quantitative formation of strongly luminescent perylene derivative. Arene-azaarenecyclynes are versatile compounds. For example, they exhibit intense luminescence in spite of the meta-bonding structure, providing the circular luminophore. Also they serve as receptors for special metal, organic, and inorganic substrates. The observed molecular functions are valuable for scientific and practical application.

Journal Article↗

PubMed2003

The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy.

BACKGROUND: Overexposure to cyclosporine is a risk factor for chronic allograft nephropathy (CAN) and dose reduction has been advocated. The purpose of this study was to determine the impact of adding the non-nephrotoxic immunosuppressant, rapamycin, after cyclosporine dose reduction in renal-allograft recipients with CAN. METHODS: Thirty-one patients with biopsy-confirmed CAN were prospectively randomized to receive a 40% cyclosporine dose reduction with (rapamycin, n=16) or without (control, n=15) the addition of rapamycin 2 mg/day. Renal function and side-effect parameters were assessed. Patients had renal allograft biopsies taken at recruitment and after 6 months. Glomeruli were isolated from these and underwent total mRNA extraction followed by RT-PCR-ELISA to assess transforming growth factor-beta1, collagen III, TIMP-1, TIMP-2, and matrix metalloproteinase-2 expression. Samples were also stained with Sirius red and the percentage interstitial volume fraction quantified by computerized histomorphometric analysis. Data are presented as mean (+/-SD). RESULTS: Patient characteristics and cyclosporine trough levels after dose reduction (rapamycin 68 [+/-21] vs. control 56 [+/-19] ng/mL, P=NS) were similar in both groups. Rapamycin patients had a significant fall in Cr-51 radioisotope glomerular filtration rate (31.6 [+/-8.9] to 27.3 [+/-8.6] mL/min, P<0.01) that was not significant in controls (29.5 [+/-10.4] to 27.0 [+/-8.0] mL/min, P=NS). Transforming growth factor-beta1 expression fell over time in control but remained constant in rapamycin patients. Conversely collagen III expression increased over the 6-month follow-up in rapamycin patients but not in controls. Both had comparable increases in TIMP-1 and matrix metalloproteinase-2 but only rapamycin patients developed a significant increase in TIMP-2. Sirius red-stained interstitial volume fraction fell over the study in controls (15.3-11.2%, P=0.06) but not in rapamycin patients (16.2-16.3%, P=NS). CONCLUSION: Rapamycin (2 mg/day) did not improve functional, molecular, or histological outcome in patients with CAN after cyclosporine dose reduction. Further studies involving larger numbers of patients are necessary to confirm these findings.

Adult↗

PubMed1999

Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone.

The human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models. In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-kappaB pathway of transcriptional activation. The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-kappaB or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-kappaB pathway may be critical.

CD4-Positive T-Lymphocytes↗

PubMed1989

Determination of the apparent functional molecular mass of the hepatocellular sodium-dependent taurocholate transporter by radiation inactivation.

The apparent target size of the sodium-dependent taurocholate transporter in basolateral rat liver plasma membrane vesicles, showing overshooting taurocholate uptake in the presence of sodium was estimated by radiation inactivation. Radiation at -105 to -120 degrees C and 2.5 Mrad/min causes a dose-dependent monoexponential reduction of the overshoot of taurocholate uptake in the presence of sodium. In contrast, taurocholate transport in the absence of sodium and taurocholate permeation at 4 degrees C remained totally unaffected by the radiation dose, indicating that the passive permeability of the membrane towards taurocholate remained unaffected. Radiation inactivation by high-energy electrons provides information about the size of the functional unit of the transporter in situ. The target size determined represents the size of the radiation-sensitive mass which is compact enough for significant energy transfer to occur within all parts of the transport system. The minimal function molecular mass was determined to be 170 kDa for the sodium-dependent taurocholate transporter. To prove the validity of radiation inactivation data four internal standard enzymes were tested under identical conditions.

Animals↗