PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Intrinsically disordered protein”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources
PubMed2006

Structural and functional properties of mouse proNGF.

The unprocessed pro-form of the NGF (nerve growth factor), proNGF (NGF precursor, without signal peptide), has been suggested to have additional functions distinct from its role as a promoter of protein folding, i.e. apoptosis and/or neurotrophic activity. Aiming to gain insights into the specific molecular interactions that mediate proNGF biological activity and into the structural determinants stabilizing its pro-region, rm-proNGF (recombinant mouse proNGF) was expressed in Escherichia coli, refolded in vitro and characterized by physicochemical methods. X-ray solution scattering measurements (small angle X-ray scattering) revealed that rm-proNGF is dimeric in solution and appears to be anisometric when compared with the compact structure of the NGF dimer. Two structural models, a globular crab-like shape and an elongated rod-like shape, equally fit to the experimental results, pointing to an intrinsically structural disordered pro-region of NGF. The models obtained allowed the interpretation of TrkA (tropomyosin receptor kinase A) binding and activation assays in cell cultures, shedding new light on the key role of proNGF in neuronal survival and neurodegeneration.

Animals↗
PubMed2002

Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression.

In a transgenic mouse model of the neurodegenerative disorder Huntington's disease (HD), age-dependent neurologic defects are accompanied by progressive alterations in glucose tolerance that culminate in the development of diabetes mellitus and insulin deficiency. Pancreatic islets from HD transgenic mice express reduced levels of the pancreatic islet hormones insulin, somatostatin, and glucagon and exhibit intrinsic defects in insulin production. Intranuclear inclusions accumulate with aging in transgenic pancreatic islets, concomitant with the decline in glucose tolerance. HD transgenic mice develop an age-dependent reduction of insulin mRNA expression and diminished expression of key regulators of insulin gene transcription, including the pancreatic homeoprotein PDX-1, E2A proteins, and the coactivators CBP and p300. Disrupted expression of a subset of transcription factors in pancreatic beta cells by a polyglutamine expansion tract in the huntingtin protein selectively impairs insulin gene expression to result in insulin deficiency and diabetes. Selective dysregulation of gene expression in triplet repeat disorders provides a mechanism for pleiotropic cellular dysfunction that restricts the toxicity of ubiquitously expressed proteins to highly specialized subpopulations of cells.

Aging↗
PubMed2003

The antiphospholipid syndrome and atherosclerosis: clue to pathogenesis.

Regulation of blood vessels is intrinsically tied to inflammatory signaling. Recent research suggests that chronic inflammation is associated with atherosclerosis risk. The antiphospholipid syndrome is a prototypic autoimmune disease. Disturbance of blood vessel homeostasis in this disorder may increase risk for atherosclerosis by mechanisms that are direct (through antibody targeting of blood vessel-regulating proteins) or indirect (via inflammatory mechanisms that have recently been implicated in autoantibody-mediated thrombosis).

Antiphospholipid Syndrome↗
PubMed2005

[Belated decompensation of an Imerslund-Grasbeck disease].

Imerslund-Gräsbeck disease is an autosomic recessive disease characterised by a megaloblastic anemia due to a vitamin B12 deficiency and by a moderate proteinuria without kidney failure. It is caused by the malabsorption of Cobalamin-intrinsic factor complex bringing into play cubulin and other proteins (megaline, amnioless), some mutations of which are described at present. We report herein the observation of a child whose diagnosis was made belatedly during an acute decompensation with biological hemophagocytic syndrome. Its evolution was marked by the appearance of neurological disorders at the beginning of the vitamin B12 substitution treatment. These disorder regressed as the dosage was increase. The purpose of this observation is to recapitulate the main characteristics of this disease and to review the current data.

Anemia, Megaloblastic↗
PubMed1993

Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by progressive and variable involvement of tissues predominantly derived from the neural crest and a predisposition toward malignancies. The NF1 gene encodes neurofibromin, a GTPase-activating protein containing a GAP-related domain (NF1-GRD) that is capable of down-regulating ras by stimulating its intrinsic GTPase activity. We report a homozygous deletion of most of NF1 in one of eight malignant melanoma cell lines leading to loss of detectable mRNA and protein, as well as the apparent absence of protein and mRNA in another melanoma. This data suggests that NF1 can function as a tumour suppressor gene in the development or progression of malignant melanoma.

Chromosome Mapping↗
PubMed2002

The glycosylphosphatidylinositol anchor and paroxysmal nocturnal haemoglobinuria/aplasia model.

Paroxysmal nocturnal haemoglobinuria (PNH) is unique because it is an acquired haemolytic anaemia, resulting from an intrinsic red cell membrane disorder. The disease has been shown to be due to a somatic mutation of the phosphatidylinositol glycan complementation class A (pig-a) gene at the level of the haemopoietic stem cell. The defect in synthesis of the glycosylphosphatidylinositol (GPI) anchor results in a deficiency of all proteins that are GPI-bound to red cell, leucocyte and platelet membranes. The function of these proteins is extremely varied but a critical role is the protection of the cell from complement and it is the unopposed action of the complement cascade that results in the intravascular haemolysis and venous thrombosis which are hallmarks of the disease. The relationship between PNH and aplastic anaemia remains intriguing. It appears likely that an insult to a haemopoietic progenitor alters it in such a way that it becomes vulnerable to immune-mediated attack by cytotoxic T cells and/or cytokines. This attack requires one or more GPI-anchored molecules to be effective. Thus a GPI-negative clone would be at a relative advantage, and it is the balance between bone marrow impairment and proliferation of the GPI-negative clone(s) that determines the clinical picture. Prospects for molecular therapy continue to improve. Cell-to-cell transfer of GPI-linked proteins has been demonstrated in murine studies and recombinant CD59 has been expressed on GPI-deficient lymphocytes in vitro. Gene therapy remains a tantalising possibility, although a greater understanding of the pathophysiology of PNH is required, as well as advances in gene therapy techniques, before such an approach can be seriously considered.

Anemia, Aplastic↗
PubMed1990

Chronic myelogenous leukemia as a model for the genetic basis of cancer.

CML has provided a model for the genetic basis of human neoplasia. Since 1960 with the discovery of the Ph chromosome, study of this disease has provided a conceptual basis for viewing cancer as a clonal disorder occurring at the stem cell level and associated with intrinsic genetic defects which contribute to abnormal growth regulation. Although several oncogenes have been identified through the study of tumor-producing retroviruses in animals, discovery of the BCR/ABL translocation, the altered 8.5 kb BCR/ABL transcript, and the hybrid BCR/ABL P210 protein with enhanced tyrosine kinase activity has provided one of the first examples of a human neoplasm in which structural alterations in a normal cellular gene might lead to malignant transformation. However, it is likely that P210 is necessary but not sufficient for the full spectrum of malignant behavior observed in this disease. Investigation of the molecular events that are associated with the additional cytogenetic abnormalities of blast phase will most likely reveal alterations of other important growth regulatory genes which contribute to the multistep nature of malignant transformation in CML.

Chromosomes, Human, Pair 22↗
PubMed1986

Forskolin (cyclic adenosine monophosphate)-dependent protein phosphorylation in isolated gastric glands.

Improved management of peptic ulcer disease requires elucidation of cellular processes underlying gastric secretion. The intracellular execution of regulatory commands to secretory cells involves protein phosphorylation. We studied cyclic adenosine monophosphate (cAMP)-dependent phosphorylation in isolated gastric glands (IGGs) using forskolin, which directly stimulates adenylate cyclase. Forskolin stimulated secretion by both parietal and chief cells. In a separate set of studies, IGGs were incubated for 45, 90, and 105 minutes in modified Ham's F-10 medium containing orthophosphate labeled with phosphorus 32. The forskolin (10(-4) M) was added to some IGG preparations at 90 minutes. The reaction was terminated with sodium dodecyl sulfate and boiling. The proteins were resolved on sodium dodecyl sulfate-polyacrylamide gels, stained with Coomassie blue, and autoradiographed. Incorporation of phosphorus 32 increased progressively at 45, 90, and 105 minutes. Forskolin enhanced phosphorylated bands around 92 kilodaltons. These results are consistent with the major role of cAMP in the regulation of gastric cellular function. The study of cAMP-stimulated phosphorylation may be an important tool in the elucidation of intracellular regulatory mechanisms of gastric secretion. Modulation of these mechanisms may be the ideal therapeutic modality for treatment of acid-secretory disorders.

Aminopyrine↗
PubMed1969

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin.

A large family has been studied, 11 of whose members have half-normal plasma concentrations of biological prothrombin activity. The pattern of inheritance is autosomal. By use of a specific immunoassay, affected family members have been shown to possess normal quantities of immunoreactive prothrombin, whose immunologic properties seem identical with those of the normal zymogen. Prothrombin isolation from the plasma of one such individual gave normal yields of protein but half-normal amounts of prothrombin activity. Activation of this material in the "intrinsic" and "extrinsic" systems, in concentrated sodium citrate, or by trypsin, gives rise to half, or less, of the thrombin clotting and esterase activities expected from a comparable normal prothrombin preparation. During the clotting of blood from an affected individual, all material with the mobility of prothrombin disappears. Immunoelectrophoresis of the serum reveals a normal nonthrombin "pro piece," and an additional activation product with an electrophoretic mobility intermediate between that of prothrombin and of "pro piece." These results suggest that affected individuals are heterozygotes in whom half the prothrombin molecules synthesized are structurally abnormal, since they undergo some alterations during activation, but are incapable of releasing the active enzyme, thrombin.

Adolescent↗
PubMed1978

Peripheral amino acid levels in patients with cancer.

Peripheral arterial and venous whole blood amino acid concentrations were determined in four groups of subjects after an overnight fast 1) normal people, 2) patients with cancer who had not lost body weight, 3) subjects with cancer who had lost more than 20% of body weight and 4) patients who had lost more than 20% of body weight from diminished intake due to cause other than cancer. Comparison of the arterial blood levels in the four groups showed that patients with cancer and weight loss had amino acid patterns different from patients who were malnourished for other reasons. Branched chain amino acids were normal in patients with malignant disease. Some gluconeogenic amino acids were reduced as in other subjects with weight loss but the characteristic rise in glycine seen with malnutrition was not present. Arterio venous differences in whole blood across the forearm showed no evidence of increase in venous excess in patients with progressive malignant disease, indicating no excessive protein catabolism in muscle tissue. The data are consistent with increased gluconeogenesis in malnourished cancer subjects, probably due to intrinsic change in hepatic metabolism.

Amino Acids↗
PubMed1982

Comparative effects of melittin and its hydrophobic and hydrophilic fragments on bilayer organization by Raman spectroscopy.

For bilayer systems consisting of 1,2-dimyristoyl phosphatidylcholine (DMPC) incubated with melittin, a polypeptide capable of integrating itself within the membrane, temperature profiles derived from Raman spectroscopic data indicate the existence of an immobilized lipid annulus surrounding the polypeptide. In particular, temperature profiles derived from C--H, C--D and C--C stretching mode parameters for 25:1, 14:1 and 10:1 lipid:protein mole ratios exhibit two order-disorder transitions. The primary (lower) gel to liquid crystalline phase transition is depressed when polypeptide concentration is increased. The concentration-independent higher temperature transition is associated with a fluidization of the immobilized boundary lipids present at the lipid-polypeptide interface within the bilayer. We estimate that five to seven lipids are involved in this discrete boundary layer around the inserted membrane component. The behavior of the intrinsic hydrophobic (residues 1-19) and of the extrinsic hydrophilic (residues 20-26) portions of melittin in the bilayer is compared with the properties of the intact polypeptide. We emphasize evidence that both intrinsic and extrinsic components immobilize lipids contiguous to the polypeptide.

Animals↗
PubMed2006

Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets.

All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short alpha-helical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Evaluation of preconditioning treatments to protect near-pure cortical neuronal cultures from in vitro ischemia induced acute and delayed neuronal death.

We evaluated the efficacy of cycloheximide, heat stress, NMDA receptor blockade (MK801/AP-5), oxygen--glucose deprivation, hypoxia, hypothermia and TNFalpha preconditioning to protect cortical neurons from in vitro ischemic insults that result in acute necrotic and delayed apoptotic neuronal death. Preconditioning treatments were performed 22--24 h before in vitro ischemia. In vitro ischemia was carried out in 96-well microtitre strip-plates by washing neuronal cultures with a balanced salt solution containing 25 mM 2-deoxy-D-glucose and incubating in an anaerobic chamber. Glutamate receptor blockers were present during in vitro ischemia to induce delayed neuronal death. Cycloheximide, heat stress, MK801 and oxygen--glucose deprivation preconditioning were neuroprotective in both acute and delayed in vitro ischemic neuronal death models. AP-5 preconditioning and a 12 h post-MK801 preconditioning interval protected neurons from acute ischemic neuronal death only. Hypoxia, TNFalpha and hypothermic preconditioning provided no neuronal protection in the in vitro ischemia models. This study has confirmed for the first time that several preconditioning treatments can protect neurons from in vitro ischemia induced acute necrotic and delayed apoptotic neuronal death. In addition, a unique feature of this study is the finding that preconditioning could be induced in near-pure primary cortical neuronal cultures, thus confirming that ischemic tolerance is an intrinsic property of neurons and provides a simplified culture system for identifying neuroprotective proteins.

Animals↗
PubMed2005

Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo.

Amnionless (AMN) and cubilin gene products appear to be essential functional subunits of an endocytic receptor called cubam. Mutation of either gene causes autosomal recessive Imerslund-Gräsbeck syndrome (I-GS, OMIM no. 261100) in humans, a disorder characterized by selective intestinal malabsorption of cobalamin (vitamin B12) and urinary loss of several specific low-molecular-weight proteins. Vital insight into the molecular pathology of I-GS has been obtained from studies of dogs with a similar syndrome. In this work, we show that I-GS segregates in a large canine kindred due to an in-frame deletion of 33 nucleotides in exon 10 of AMN. In a second, unrelated I-GS kindred, affected dogs exhibit a homozygous substitution in the AMN translation initiation codon. Studies in vivo demonstrated that both mutations abrogate AMN expression and block cubilin processing and targeting to the apical membrane. The essential features of AMN dysfunction observed in vivo are recapitulated in a heterologous cell-transfection system, thus validating the system for analysis of AMN-cubilin interactions. Characterization of canine AMN mutations that cause I-GS establishes the canine model as an ortholog of the human disorder well suited to studies of AMN function and coevolution with cubilin.

Animals↗
PubMed2001

Primary immunodeficiency mutation databases.

Primary immunodeficiencies are intrinsic defects of immune systems. Mutations in a large number of cellular functions can lead to impaired immune responses. More than 80 primary immunodeficiencies are known to date. During the last years genes for several of these disorders have been identified. Here, mutation information for 23 genes affected in 14 immunodefects is presented. The proteins produced are employed in widely diverse functions, such as signal transduction, cell surface receptors, nucleotide metabolism, gene diversification, transcription factors, and phagocytosis. Altogether, the genetic defect of 2,140 families has been determined. Diseases with X-chromosomal origin constitute about 70% of all the cases, presumably due to full penetrance and because the single affected allele causes the phenotype. All types of mutations have been identified; missense mutations are the most common mutation type, and truncation is the most common effect on the protein level. Mutational hotspots in many disorders appear in CPG dinucleotides. The mutation data for the majority of diseases are distributed on the Internet with a special database management system, MUTbase. Despite large numbers of mutations, it has not been possible to make genotype-phenotype correlations for many of the diseases.

Alleles↗
PubMed2003

Binding-induced folding transitions in calpastatin subdomains A and C.

Calpastatin, the endogenous inhibitor of calpain, is an intrinsically unstructured protein proposed to undergo folding transitions upon binding to the enzyme. As this feature has never been experimentally tested, we have set out to characterize the conformation of two peptides corresponding to its conserved subdomains, A and C, known to interact with calpain in a Ca(2+)-dependent manner. The peptides are disordered in water but show a high propensity for alpha-helical conformation in the presence of trifluoroethanol. The conformational transition is sensitive to Ca(2+), and is clearly seen upon binding of the peptides to the enzyme. Secondary-structure prediction of all calpastatin sequences shows that the helix-forming potential within these regions is a conserved feature of the inhibitor. Furthermore, quantitative data on the binding strength of calpastatin fragments reveal that binding of the inhibitor is accompanied by a large decrease in its configurational entropy. Taken together, these observations point to significant binding-induced local folding transitions in calpastatin, in a way that ensures highly specific, yet reversible, action of the inhibitor.

Animals↗
PubMed2003

Potential new targets for antithrombotic therapy.

Thrombosis is the collective term for diseases caused by the localized accumulation of circulating blood elements within the vasculature that result in vessel occlusion. Conventional antithrombotic drugs can inhibit thrombus growth by targeting coagulation pathways (e.g., heparin, warfarin) or platelet-dependent mechanisms (e.g., aspirin, clopidogrel). Thrombolytic agents (e.g., streptokinase) are used to degrade thrombi in situ, thereby restoring the blood flow. Despite advances, the search for new strategies continues because existing treatments impair hemostasis, and must be administered at dose levels that do not achieve maximum efficacy. Only a few drugs are used at markedly efficacious doses, for short periods of time in closely watched clinical situations, such as interventional cardiology and surgery. Ideally, new targets for therapy would lead to the development of agents that are specific for thrombus-forming mechanisms without affecting hemostasis. In the absence of such agents, new products should preferentially inhibit the thrombotic process at doses that are relatively safe. The symptomatology of naturally occurring or experimentally-induced alterations of relevant hemostatic pathways can serve as basis for target selection. Hemostatic disorders that are compatible with life, do not pose a significantly increased risk of bleeding, but potentially protect against thrombosis provide guidance for rational design strategies. Theoretical considerations and recent experimental data suggest that: 1) inhibition of intrinsic coagulation pathway activity, 2) reduction of circulating platelet count, or 3) activation or enhancement of endogenous protein C or thrombolytic pathways could improve antithrombotic therapy.

Animals↗