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Structural insights into Plasmodium PPIases.

Malaria is one of the most prevalent infectious diseases posing a serious challenge over the years, mainly owing to the emergence of drug-re … ed to inhibit the growth of the malarial parasite, Plasmodium falciparum. Peptidyl prolyl cis/trans isomerases (PPIases), comprising cylcophilins and FK506-binding proteins (FKBPs), the specific target of these drugs, were identified in the Plasmodium parasite and proposed as an antimalarial drug target. We previously attempted to decipher the structure of t …

N-linked sugar-regulated protein folding and quality control in the ER.

Asparagine-linked glycans (N-glycans) are displayed on the majority of proteins synthesized in the endoplasmic reticulum (ER). Removal of the outermost glucose residue recruits the lectin chaperone malectin possibly involved in a first triage of defective polypeptides. Removal of a second glucose promotes engagement of folding and quality control machineries built around the ER lectin chaperones calnexin (CNX) and calreticulin (CRT) and including oxidoreductases and peptidyl-prolyl isomerases. Deprivation of the last glucose residue dictates the release of N-glycosylated polypeptides from the …

FKBP133: a novel mouse FK506-binding protein homolog alters growth cone morphology.

FK506-binding proteins are the peptidyl prolyl cis-trans isomerases that are involved in various intracellular events. We characterized a novel mouse FK506-binding protein homolog, FKBP133/KIAA0674, in the developing nervous system. FKBP133 contains a domain similar to Wiskott-Aldrich syndrome protein homology region 1 (WH1) and a domain homologous to FK506-binding protein motif. FKBP133 was predominantly expressed in cerebral cortex, hippocampus, and peripheral ganglia at embryonic day 18.5. FKBP133 protein was distributed in the axonal shafts and was partially co-localized with F-actin in th…

[Retinoic acid and steroidogenesis].

When Wistar and Sprague-Dawley rats fed from weaning on a vitamin A and provitamin A deficient diet are supplemented with retinoic acid, they mature into adults whose general physical conditions and weight are comparable with those of retinol supplemented animals. However, the adrenal cortex, testes and ovaries delta 5-3 beta hydroxysteroid deshydrogenases-delta 5-delta 4-3-oxosteroide isomerases are in all cases strongly decreased compared with those of retinol supplemented animals. These results are reproducible only if the mothers' reserves in vitamin A are about 50 gamma/g of hepatic tissu…

Protein structural properties, proteomics and flavor characterization analysis of rice during cooking.

This study analyzed the changes in rice protein structure, protein profiling, and flavor profiles at different cooking stages, as well as their interrelationships. In the continuous cooking process, changes in protein structure characteristics were mainly reflected in the boiling and stewing stages. Protein unfolding and aggregation were important reasons for significant changes in protein structural characteristics. Protein disulfide isomerases and glycine-rich RNA-binding proteins can be used as marker factors to characterize the changes during rice cooking. The concentrations of aldehydes, …

Advances in understanding the molecular mechanisms of venous thrombosis.

Venous thromboembolism (VTE) represents a leading cause of global mortality, however, the determinants that contribute to thrombus developme … e review the accumulating evidence that blood cells, contact pathway factors and protein disulphide isomerases all play key roles in VTE development. Finally, we discuss new insights into the role of metabolites arising from commensal gut bacteria and their potential role in facilitating VTE. This overview provides an update on these state-of-the-art develop …

Further delineation of FKBP14-related Ehlers-Danlos syndrome: A patient with early vascular complications and non-progressive kyphoscoliosis, and literature review.

FKBP14-related Ehlers-Danlos syndrome (EDS) is an extremely rare recessive connective tissue disorder described for the first time in 2012 by Baumann and coworkers. The causal gene, FKBP14, encodes a member of the F506-binding family of peptidyl-prolyl cis-trans isomerases. The paucity of patients described so far makes this disorder poorly defined at clinical level. Here, we report an additional pediatric patient, who is compound heterozygous for a recurrent and a novel FKBP14 mutation, and compare his phenotype with those available in literature. This evaluation confirms that kyphoscoliosis …

Study of urinary proteomes in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked genetic disorder with deficient α-galactosidase A activity. The main aim of this work was to investigate possible differences in urine proteins between healthy controls and AFD patients and to identify abnormal proteins as potential biomarkers of disease. MATERIAL AND METHODS: We studied 2D electrophoresis images of urine samples collected from AFD patients and healthy subjects. The proteins were separated using isoelectric focusing method followed by SDS-PAGE. The proteins were then visualized by silver staining and characterized by mat

Biochemical characterization of Leishmania (Viannia) braziliensis and Leishmania (Viannia) peruviana by isoenzyme electrophoresis.

Leishmanial organisms isolated from 24 patients with Andean cutaneous leishmaniasis (uta) and from 7 with sylvatic leishmaniasis in both cutaneous and mucosal forms were characterized on the basis of their isoenzyme profiles for 13 enzymes using both cellulose acetate (CA) and thin-layer starch gel (TLS) electrophoretic techniques. Malate dehydrogenase (MDH) after electrophoresis on CA or TLS and mannose phosphate isomerase (MPI) on TLS were the only enzymes of 13 examined which discriminated between the organisms from patients with uta (L. (V.) peruviana) and those with sylvatic leishmaniasis

Multiple mechanisms for regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5----delta 4-isomerase, 17 alpha-hydroxylase/C17-20 lyase cytochrome P450, and cholesterol side-chain cleavage cytochrome P450 messenger ribonucleic acid levels in primary cultures of mouse Leydig cells.

The regulation of mRNA levels for delta 5-3 beta-hydroxysteroid dehydrogenase/delta 5----delta 4-isomerase (3 beta HSD), 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 (P450(17 alpha] and cholesterol side-chain cleavage cytochrome P450 (P450scc) was studied in primary cultures of mouse Leydig cells. Treatment of Leydig cells with 8-bromo-cAMP (cAMP) was essential for expression of P450(17 alpha) mRNA, but not for 3 beta HSD. Treatment with cAMP caused a decrease in basal levels of 3 beta HSD mRNA. The addition of aminoglutethimide (AG), an inhibitor of cholesterol metabolism, to the cAMP-tr

Potent Inducers of Paraptosis through Electronic Tuning of Hemicyanine Electrophiles.

Paraptosis is a distinct form of programmed cell death characterized by cytoplasmic vacuolization, mitochondrial swelling, and endoplasmic r … d by its minimal interaction with well-known nucleophilic protein targets such as protein disulfide isomerases. These findings establish the hemicyanine chemical family as a promising scaffold for paraptosis research and suggest potential as a therapeutic lead for diseases where traditional apoptosis pathways are dysregulated.

The Molecular Basis of the Interaction of Cyclophilin A with α-Synuclein.

Peptidylprolyl isomerases (PPIases) catalyze cis/trans isomerization of prolines. The PPIase CypA colocalizes with the Parkinson's disease (PD)-associated protein α-synuclein in cells and interacts with α-synuclein oligomers. Herein, we describe atomic insights into the molecular details of the α-synuclein/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline 128 in the C-terminal domain of α-synuclein. Strikingly, we reveal a second CypA-binding site formed by the hydrophobic sequence 47 GVVHGVATVA56 , termed PreNAC. The 1.38 Å crystal structure of the CypA/Pre…

High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila─A Comparison.

Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila, express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion. The affinity of a series of pipecolic acid-type MIP inhibitors was evaluated

Development of a genetic assay to distinguish between Leishmania viannia species on the basis of isoenzyme differences.

BACKGROUND: Tegumentary leishmaniasis in Latin America is caused mainly by Leishmania viannia braziliensis complex parasites. L. braziliensis and Leishmania viannia peruviana are the 2 predominant Leishmania species in Peru. L. braziliensis is more virulent, because it can cause mucocutaneous leishmaniasis, known as espundia, that results in severe facial destruction. Early identification of the species that causes the initial cutaneous infection would greatly help to prevent mucocutaneous leishmaniasis, because it would allow more aggressive treatment and follow-up. However, because of the cl

Pin1 colocalization with phosphorylated tau in Alzheimer's disease and other tauopathies.

Pin1, a peptidyl-prolyl isomerase binds to mitotic serine or threonine phosphoproteins. In Alzheimer's disease (AD) evidence points to the reactivation of mitosis in vulnerable neurons. Tangles composed of hyperphosphorylated tau contain phosphorylated Thr231 (pThr231 tau), which occurs to a greater extent in the AD brain than in the normal brain, and Pin1 has been shown to bind pThr231 tau. Here, Pin1 distribution in AD, and its colocalization with pThr231 tau in AD, FTDP-17 (P301L), Pick's disease (PiD), and PSP was investigated using TG-3, a monoclonal antibody to conformationally altered p

Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.

Osteogenesis imperfecta is a heritable disorder that causes bone fragility. Mutations in type I collagen result in autosomal dominant osteogenesis imperfecta, whereas mutations in either of two components of the collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-hydroxylase 1 [P3H1]) cause autosomal recessive osteogenesis imperfecta with rhizomelia (shortening of proximal segments of upper and lower limbs) and delayed collagen folding. We identified two siblings who had recessive osteogenesis imperfecta without rhizomelia. They had a homozygous start-cod

Isosexual precocious pseudopuberty secondary to a feminizing adrenal tumor.

We report a 2 10/12-yr-old girl with precocious pseudopuberty due to a feminizing adrenal carcinoma without Cushing's syndrome. The patient had marked elevation of plasma concentrations of the delta 5 adrenal steroids dehydroepiandosterone and dehydroepiandrosterone sulfate and increased levels of androstenedione, estrone, estradiol, and testosterone. Adrenal microsomal 3 beta-hydroxysteroid dehydrogenase-isomerase 17-hydroxylase, 17,20-desmolase, and 21-hydroxylase activities in the tumor and adjacent normal adrenal gland were measured. The tumor had approximately normal levels of 17-hydroxyl

Logical Exploration of Cinnamoyl-Containing Nonribosomal Peptides via Metabologenomic Targeting and Regulator Overexpression.

A targeted method for discovering cinnamoyl-containing nonribosomal peptides (CCNPs), a unique class of bioactive compounds, was devised by using cinnamoyl isomerase, a key enzyme in the biosynthesis of the cinnamoyl moiety, as a genome mining probe. A total of 39 hit strains were obtained, including 35 from polymerase chain reaction-based screening of the in-house bacterial library (2.5% of 1400 strains) targeting the cinnamoyl isomerase-encoding gene and 4 from the genome mining of online databases. Sequence similarity networking and phylogenetic analyses of the isomerase amplicons (∼530 bp)

FK506-Binding Protein 11 Is a Novel Plasma Cell-Specific Antibody Folding Catalyst with Increased Expression in Idiopathic Pulmonary Fibrosis.

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lympha

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… This process is strictly dependent on an ER-resident protein folding machinery consisting of molecular chaperones, peptidyl-prolyl cis - trans isomerases (PPIases), disulfide isomerases, and glycosyl transferases [ 2 , 3 ]. … Recombinant PPIB, commonly accepted as antibody peptidyl-prolyl isomerase (PPIase) [ 2 ], was used as positive control. …

Quantification of the Redox State of Integrin Disulfide Bonds.

We have developed a mass spectrometry-based method to quantify the redox state of protein disulfide bonds using a pair of isotopic alkylators. This technique can be applied in several contexts to investigate disulfide bond regulation in integrins. It may be used to identify disulfide-bond targets of vascular thiol isomerases, such as the two disulfide bonds in the β2 subunit of the integrin Mac-1 that are modulated by protein disulfide isomerase (PDI), or to evaluate the redox state of wild-type and mutant αIIbβ3 integrins recombinantly expressed in mammalian cells. Additionally, the method en…