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At least 631 records · Page 35Linked to original sources
PubMed2001

Global minimization of an off-lattice potential energy function using a chaperone-based refolding method.

A global energy minimization method based on what is known about the mechanisms of the GroEL/GroES chaperonin system is applied to two 22-mers of an off-lattice protein model whose native states are beta-hairpins and which have structural similarity to short peptides known to interact strongly with the GroEL substrate binding domain. These model substrates have been used by other workers to test the effectiveness of a number of global minimization techniques, and are regarded as providing a significant challenge. The minimization method developed here is progressively elaborated from an initial simple form that targets exposed hydrophobic regions for unfolding to include a refolding phase that encourages the later recompactification of partly unfolded substrate; this refolding phase is seen to be crucial in the successful application of the method. The optimal handling of hydrophilic monomers within the model is also systematically explored, and it is seen that the best interpretation of their role is one that allows the chaperonin model to operate in "proofreading" mode whereby misfolded substrates are recognized by their surface exposure of a large proportion of hydrophobic monomers. The final version of the model allows native-like structures to be found quickly, on average for the two 22-mer substrates after 6 or 7 chaperone contacts. These results compare very favorably with those that have been obtained elsewhere using generic global minimization methods such as those based on thermal annealing. The paper concludes with a discussion of the place of the technique within the general category of hypersurface deformation methods for global minimization, and with suggestions as to how the chaperone-based method developed here could be elaborated so as to be effective on longer substrate chains that give rise to more complex tertiary structures in their native states.

Biopolymers↗
PubMed2000

Suppression of T cell function: a potential role for transcriptional repressor ICER.

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of -160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numerous other cytokines and chemokines.

Cell Division↗
PubMedDate not supplied

Deciphering the human nucleolar proteome.

Nucleoli are plurifunctional nuclear domains involved in the regulation of several major cellular processes such as ribosome biogenesis, the biogenesis of non-ribosomal ribonucleoprotein complexes, cell cycle, and cellular aging. Until recently, the protein content of nucleoli was poorly described. Several proteomic analyses have been undertaken to discover the molecular bases of the biological roles fulfilled by nucleoli. These studies have led to the identification of more than 700 proteins. Extensive bibliographic and bioinformatic analyses allowed the classification of the identified proteins into functional groups and suggested potential functions of 150 human proteins previously uncharacterized. The combination of improvements in mass spectrometry technologies, the characterization of protein complexes, and data mining will assist in furthering our understanding of the role of nucleoli in different physiological and pathological cell states.

Cell Nucleolus↗
PubMed2002

Genome-wide distribution and potential regulatory functions of AtATE, a novel family of miniature inverted-repeat transposable elements in Arabidopsis thaliana.

A study of transgenic promoter::beta-glucuronidase lines showed that the promoters of the two Arabidopsis ARGININE DECARBOXYLASE paralogues, ADC1 and ADC2, exhibited extremely different patterns of activity. One major feature of the promoter of ADC1 was the presence of a novel transposable element, which was shown to possess all of the characteristics of Miniature Inverted-repeat Transposable Elements (MITEs), and to be present in 26 full-length copies and 1617 partial copies and fragments distributed throughout the Arabidopsis genome. TRANSFAC analysis showed that this transposable element possesses a significant number of transcription-factor binding motifs. A bioinformatics approach based on a suffix-tree compilation was used to obtain an exhaustive description of exact copy numbers and positions of the element in the Arabidopsis genome. The distribution among the chromosomes was non-random, and a significant number of copies were found in regions flanking genes. Full-length copies of the transposable element were detected in the immediate vicinity of 22 genes, either upstream or downstream.

Arabidopsis↗
PubMed1988

The conformation of calmodulin: a substantial environmentally sensitive helical transition in Ca4-calmodulin with potential mechanistic function.

The conformation of Ca4-calmodulin in solution, as assessed by far-UV peptide circular dichroism, contains significantly less alpha-helix than the proposed X-ray crystal structure. We now show that Ca4-calmodulin adopts significant additional helical structure in solution in the presence of a helicogenic solvent (50%, v/v, aqueous 2,2,2-trifluoroethanol or 50%, v/v, methylpentane-5,5-diol). We suggest that the long continuous helix (residues 66-92 of the crystal structure) is not necessarily a normal feature of the calmodulin structure in solution, and may be due in part to the conditions of crystallisation. This result is supported by time-resolved tyrosine fluorescence anisotropy studies indicating that Ca4-calmodulin in solution is an essentially compact globular structure which undergoes isotropic rotational motion. We conclude that, under appropriate ionic and apolar environmental conditions, Ca4-calmodulin undergoes a substantial helical transition, which may involve residues in the central region of the molecule. Such a transition could have an important function in determining specificity and affinity in interactions of calmodulin with different target sequences of Ca2+-dependent regulatory enzymes.

Animals↗
PubMed1993

Ion channel inhibitors may function as potential modulators of cocaine binding.

The effects of NaCl, KCl and Ca2Cl were determined in a binding assay, using the analog of cocaine [3H]WIN 35,428. The addition of NaCl had no effect upon specific binding; however, Ca2Cl and to a lesser extent, KCl decreased binding. Various Na+, K+, Cl- and Ca2+ channel antagonists were tested for their ability to inhibit specific binding of [3H]WIN 35,428. Most of the Na+ channel blockers tested were of moderate affinity, the exceptions being benzamil and flunarizine. Both of these agents also show activity at the Ca2+ channel. The K+ channel blockers were of low and moderate affinity, while the Cl- channel blockers had no effect. Of the Ca2+ channel blockers tested, only pimozide demonstrated a high affinity. This was postulated to be due to its ability to act upon both L and T-type channels. These results suggest that the Ca2+ channel blockers deserve further study as potential useful therapeutic agents in the treatment of cocaine addiction.

Animals↗
PubMed1992

Carnosine: its properties, functions and potential therapeutic applications.

Carnosine and related dipeptides such as anserine are naturally-occurring histidine-containing compounds. They are found in several tissues most notably in muscle where they represent an appreciable fraction of the total water-soluble nitrogen-containing compounds. The biological role of these dipeptides are conjectural but they are believed to act as cytosolic buffering agents. Numerous studies have demonstrated, both at the tissue and organelle level, that they possess strong and specific antioxidant properties. Carnosine and related dipeptides have been shown to prevent peroxidation of model membrane systems leading to the suggestion that they represent water-soluble counterparts to lipid-soluble antioxidants such as alpha-tocopherol in protecting cell membranes from oxidative damage. Other roles ascribed to these dipeptides include actions as neurotransmitters, modulation of enzymic activities and chelation of heavy metals. Many claims have been made in respect of therapeutic actions of carnosine and histidine-containing dipeptides. These include antihypertensive effects, actions as immunomodulating agents, wound healing and antineoplastic effects. Many of these claims have not been convincingly documented nor subject to rigorous clinical evaluation. Nevertheless, there are examples where studies have shown considerable promise. One is the treatment of senile cataract in dogs and another is in acceleration of healing of surface wounds and burns to the skin. It is clear from this review that many of the effects of these histidine-containing dipeptides, especially in regard to claims for their therapeutic effects, need to be subjected to critical experimental and clinical examination. Several applications do, however, show clear evidence of being useful therapeutic agents.

Animals↗
PubMed1996

Cloning and sequence analysis of human butyrophilin reveals a potential receptor function.

Human butyrophilin was cloned and sequenced from a human breast cDNA library. The derived amino acid sequence shows 84% sequence identity and identical domain arrangements with the previously reported bovine sequence. Sequence analysis reveals an immunoglobulin constant (IgC) domain that was not previously identified in the bovine sequence. The extracellular domain composition of butyrophilin suggests a cell surface receptor function.

Amino Acid Sequence↗
PubMedDate not supplied

Acetaldehyde-modified lysozyme function: its potential implication in the promotion of infection in alcoholics.

Incubation of lysozyme with acetaldehyde (0.44 M) at room temperature for 2 h produces a 62% inhibition of enzymic activity. Because the active site cleft contains tryptophyls, asparagine, glutamine, and an arginine residue, and because acetaldehyde reacts with indoles, amides, and guanidines, it is suggested that these sites are likely ones for alkylation. The epsilon-amino groups of lysines on the surface of the molecule are also susceptible to covalent modification. Total acetylation of lysozyme has been reported to inactivate the enzyme. These results suggest the possibility that inactivation of a fraction of the lysozyme activity by acetaldehyde may decrease the effectiveness of the enzyme in chronic alcoholics, thereby leading to an increased potential for susceptibility to bacterial infection.

Acetaldehyde↗
PubMed1987

Kinetic studies on the inhibitions of mast cell chymase by natural serine protease inhibitors: indications for potential biological functions of these inhibitors.

We have found that degranulation from mast cells is specifically inhibited by the inhibitors of chymase (10). Among the natural serine protease inhibitors tested, Bowman-Birk soybean protease inhibitor, Eglin C, and human alpha 1-antichymotrypsin inhibited chymase more strongly than did chymostatin, Kunitz soybean protease inhibitor, and phosphatidylserine. Of the inhibitors tested, Bowman-Birk soybean protease inhibitor was the strongest inhibitor of chymase, its Ki value being 13.2 X 10(-9) M. Kinetic studies showed that these inhibitors were all noncompetitive inhibitors of chymase. Bowman-Birk and Kunitz soybean protease inhibitors inhibited both chymotrypsin-type and trypsin-type serine proteases but Eglin C specifically inhibited chymotrypsin-type proteases.

Animals↗
PubMed1996

Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions.

Matrilysin (MAT) is a member of the matrix metalloproteinase (MMP) family which is believed to degrade components of the extracellular matrix (ECM) during processes of tissue remodeling. Although MAT is similar to the stromelysins in its substrate specificity, and to interstitial collagenase in the crystal structure of its catalytic domain, this enzyme is unique in that it lacks the carboxy-terminal segments encoded by other MMP genes. Characterization of the human MAT gene has revealed that the promoter region contains typical MMP promoter elements such as AP-1 and PEA3, which mediate responsiveness to growth factors, oncogenes, and phorbol esters. Activated recombinant forms of human MAT cleave ECM and basement membrane proteins such as fibronectin, collagen type IV, laminin, and particularly elastin, entactin, and cartilage proteoglycan aggregates. Furthermore, MAT appears to mediate the proteolytic processing of other molecules (e.g. tumor necrosis factor alpha precursor, urokinase plasminogen activator). MAT is expressed in a variety of tumors ranging from adenomas to carcinomas and adenocarcinomas of the breast, colon, prostate, stomach, upper aerodigestive tract, lung, and skin, where it may be involved in tumor formation as well as the tissue degradation which accompanies tumor cell extravasation. Localization of MAT mRNA and protein to the tumor cells is unusual in that the majority of MMPs are produced in the stroma. This distinctive tissue-restricted pattern of MAT expression is a recapitulation of the expression pattern in normal human tissue, where MAT protein localizes to secretory and ductal epithelium in the endometrium and in various exocrine glands. In the mouse, high constitutive levels of MAT mRNA are found in epithelial cells in the uterus, small intestine, and extra-testicular ducts. Taken together, these findings suggest that MAT may have a specific role in normal gland and organ function, a possibility which can be explored further by the genetic manipulation of MAT levels in vivo.

Amino Acid Sequence↗
PubMed2004

Potential endocrine function of the glycolytic enzyme glucose-6-phosphate isomerase during implantation.

Glucose-6-phosphate isomerase (GPI) is a glycolytic enzyme that also acts as autocrine motility factor, a secreted protein that stimulates tumor cell motility. We have shown that GPI is required for embryo implantation in the domestic ferret. Here, we tested the hypothesis that GPI is produced and secreted into the bloodstream by ferret luteal cells. Plasma GPI activity increased significantly during the pre-implantation period in both pregnant and pseudopregnant ferrets. Explants from Corpus luteum (CL) and follicles of the pre-implantation period were cultured to ascertain their ability to secrete GPI. The medium of cultured luteal extracts contained significantly more GPI activity than the medium of cultured follicles, a control tissue. GPI activity in the medium increased significantly with increasing pregnancy stage, from pregnancy days 3 to 12. However, GPI activity within explant homogenates was the same in CL and follicles and at all days of pregnancy. Thus, CL but not follicles, secrete GPI during the pre-implantation period. Our findings suggest that GPI may be acting in an endocrine manner, being secreted from the CL into the blood, and acting to promote implantation, which occurs at a distant site, the uterus.

Animals↗
PubMed2003

Differential action of natural selection on the N and C-terminal domains of 2'-5' oligoadenylate synthetases and the potential nuclease function of the C-terminal domain.

2'-5' Oligoadenylate synthetases (OAS) are a family of enzymes, which are best known for their important role in interferon-dependent antiviral mechanisms, but are also involved in the regulation of apoptosis, cell growth and differentiation in vertebrates. These enzymes bind double-stranded RNA and catalyze the synthesis of 2'-5' oligoadenylates from ATP. Several 2'-5' oligoadenylate synthetase-like proteins, which lack the ability to synthesize 2'-5' A, have been recently identified in humans and mice; the functions of these inactivated OAS derivatives remain unknown. Examination of phylogenetic trees shows that OAS inactivation in mammals occurred on several independent occasions. Comparative sequence analysis of OAS, poly(A)-polymerases, TRF4/sigma-family polymerases, archaeal CCA-adding enzymes and uridilyltransferases from trypanosomes resulted in the identification of a C-terminal domain, which is conserved in all these enzymes and is distinct from the nucleotidyltransferase domain. Secondary structure prediction shows that this domain has a four-helix core, which is most closely related to the ATP-cone domain, a regulatory nucleotide-binding domain present in ribonucleotide reductases and several other enzymes and transcription regulators. These observations, taken together with the experimental evidence of nuclease activity in the TRF4/sigma-family of polymerases, suggest that the C-terminal domain of OAS and their homologs might have nuclease activity. The putative nuclease domain is preferentially conserved in OAS derivatives that lack an active nucleotidyltransferase domain and, as indicated by the analysis of the ratio of synonymous to non-synonymous substitutions, appears to be subject to purifying selection in these proteins. In contrast, phylogenetic analysis provided evidence of episodic positive selection in the mouse OAS-like proteins with inactivated nucleotidyltransferase domains, which suggests that some of these proteins might have distinct antiviral functions.

2',5'-Oligoadenylate Synthetase↗
PubMed2002

An evaluation of biomarkers of reproductive function and potential contaminant effects in Florida largemouth bass ( Micropterus salmoidesfloridanus) sampled from the St. Johns River.

The objective of this study was to describe and compare several reproductive parameters for Florida largemouth bass (Micropterus salmoides floridanus) inhabiting the St. Johns River and exposed to different types and/or degrees of contamination. Welaka was selected as the reference site in this study because of its low urban and agricultural development, Palatka is in close proximity to a paper mill plant, the Green Cove site is influenced by marine shipping activities and Julington Creek site receives discharges of domestic wastewater and storm water runoff from recreational boating marinas. For this study, bass were sampled both prior to (September 1996) and during the spawning season (February 1997). In order to characterize chemical exposure, bass livers were analyzed for up to 90 trace organics and 11 trace metal contaminants. Reproductive parameters measured included gonadosomatic index (GSI), histological evaluation of gonads and plasma concentrations of vitellogenin (VTG), 17beta-estradiol (E2) and 11-ketotestosterone (11-KT). In general, the sum of organic chemicals was highest in livers from Palatka bass and bass from Green Cove and Julington Creek had higher hepatic concentrations of low molecular polycyclic aromatic hydrocarbons and polychlorinated biphenyls when compared to fish from Welaka. Metals were more variable across sites, with highest mean concentrations found in bass from either Julington Creek (Ag, As, Cr, Cu, Zn) or Welaka (Cd, Hg, Pb, Se, Tn). Female bass from Palatka and Green Cove had lower concentrations of E2, VTG and lower GSI in relation to Welaka. Males from Palatka and Green Cove showed comparable declines in 11-KT in relation to males from Julington Creek and GSI were decreased only in Palatka males. These results indicate a geographical trend in reproductive effects, with changes being most pronounced at the site closest to the paper mill (Palatka) and decreasing as the St. Johns River flows downstream. Since reproductive alterations were most evident in bass sampled from the site closest to the paper mill discharge, it is possible that exposure to these effluents might explain at least some of the results reported here. However, the presence of reproductive alterations in fish sampled at a considerable distance from the mill discharge (Green Cove, 40 km) would suggest exposure to chemicals released from sources other than the paper mill plant. It is clear that additional studies are needed to evaluate the potential impact of these reproductive changes in populations of Florida largemouth bass inhabiting the St. Johns River.

Animals↗