The molecular interaction of 4′-iodo-4′-deoxydoxorubicin with Leu-55Pro transthyretin ‘amyloid-like’ oligomer leading to disaggregation

2000 ◽  
Vol 351 (1) ◽  
pp. 273-279 ◽  
Author(s):  
Maria Paula SEBASTIÃO ◽  
Giampaolo MERLINI ◽  
Maria João SARAIVA ◽  
Ana Margarida DAMAS
Keyword(s):  
Iodine Atom ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Intermediate Structure ◽  
Biochemical Pathway ◽  
Wild Type ◽  
Immunoglobulin Light Chain ◽  
Amyloid Load ◽  
Β Sheets ◽  
Immunoglobulin Light Chain Amyloidosis

The crystal structure of the amyloidogenic Leu-55Pro transthyretin (TTR) variant has revealed an oligomer structure that may represent a putative amyloid protofibril [Sebastião, Saraiva and Damas (1998) J. Biol. Chem. 273, 24715–24722]. Here we report biochemical evidence that corroborates the isolation of an intermediate structure, an ‘amyloid-like’ oligomer, which is most probably present in the biochemical pathway that leads to amyloid deposition and that was isolated by the crystallization of the Leu-55Pro TTR variant. 4´-Iodo-4´-deoxydoxorubicin (IDOX) is a compound that interacts with amyloid fibrils of various compositions and it has been reported to reduce the amyloid load in immunoglobulin light chain amyloidosis [Merlini, Ascari, Amboldi, Bellotti, Arbustini, Perfetti, Ferrari, Zorzoli, Marinone, Garini et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2959–2963]. In this work, we observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, undergo rapid dissociation. Moreover, under the same conditions, the orthorhombic wild-type TTR crystals are quite stable. This is explained by the different TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX binding, the same structure is not present in the crystallized wild-type protein. A theoretical model concerning the interaction of Leu-55Pro TTR with IDOX, which is consistent with the dissociation of the amyloid-like oligomer, is presented. In this model the IDOX iodine atom is buried in a pocket located between the two β-sheets of the Leu-55Pro TTR monomer with the IDOX aromatic-moiety long axis nearly perpendicular to the direction of the β-sheets.

scholarly journals Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lidan Liu ◽  
Chaim Z. Aron ◽  
Cullen M. Grable ◽  
Adrian Robles ◽  
Xiangli Liu ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Mrna Levels ◽  
Wild Type ◽  
Cytokine Mrna ◽  
Protein Levels ◽  
Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

scholarly journals A Unique Case of Combined Nodular and Tracheobronchial Amyloidosis

2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Feihong Ding ◽  
Yun Li ◽  
Shailesh Balasubramanian ◽  
Subha Ghosh ◽  
Jason N Valent ◽  
...  
Keyword(s):  
Light Chain ◽  
Systemic Disease ◽  
Amyloid Deposition ◽  
Misfolded Proteins ◽  
Immunoglobulin Light Chain ◽  
Anatomic Site ◽  
Unique Case ◽  
Pulmonary Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis ◽  
Tracheobronchial Amyloidosis

ABSTRACT Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of misfolded proteins that can affect either systemically or locally confined to one system. Pulmonary amyloidosis is rare and can be classified into three forms according to the anatomic site of involvement: nodular pulmonary amyloidosis, tracheobronchial amyloidosis and diffuse alveolar-septal amyloidosis. The former two usually represent localized amyloid disease and the latter represents systemic disease. Typically lung parenchymal and tracheobronchial amyloidosis do not present together in localized forms of pulmonary amyloidosis. Here we report a unique case of localized pulmonary immunoglobulin light-chain amyloidosis, manifested as both parenchymal nodules and tracheobronchial amyloid deposition.

scholarly journals Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Linchun Xu ◽  
Yongzhong Su
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Amyloid Fibril ◽  
Treatment Modalities ◽  
Driver Gene ◽  
Immunoglobulin Light Chain ◽  
Disease Evolution ◽  
Genetic Aberrations ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

AbstractImmunoglobulin light chain amyloidosis (AL) is an indolent plasma cell disorder characterized by free immunoglobulin light chain (FLC) misfolding and amyloid fibril deposition. The cytogenetic pattern of AL shows profound similarity with that of other plasma cell disorders but harbors distinct features. AL can be classified into two primary subtypes: non-hyperdiploidy and hyperdiploidy. Non-hyperdiploidy usually involves immunoglobulin heavy chain translocations, and t(11;14) is the hallmark of this disease. T(11;14) is associated with low plasma cell count but high FLC level and displays distinct response outcomes to different treatment modalities. Hyperdiploidy is associated with plasmacytosis and subclone formation, and it generally confers a neutral or inferior prognostic outcome. Other chromosome abnormalities and driver gene mutations are considered as secondary cytogenetic aberrations that occur during disease evolution. These genetic aberrations contribute to the proliferation of plasma cells, which secrete excess FLC for amyloid deposition. Other genetic factors, such as specific usage of immunoglobulin light chain germline genes and light chain somatic mutations, also play an essential role in amyloid fibril deposition in AL. This paper will propose a framework of AL classification based on genetic aberrations and discuss the amyloid formation of AL from a genetic aspect.

scholarly journals Beyond the plasma cell: emerging therapies for immunoglobulin light chain amyloidosis

Blood ◽  
2016 ◽  
Vol 127 (19) ◽  
pp. 2275-2280 ◽  
Author(s):  
Brendan M. Weiss ◽  
Sandy W. Wong ◽  
Raymond L. Comenzo
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Organ Damage ◽  
Immunoglobulin Light Chain ◽  
Organ Function ◽  
Fatal Disease ◽  
Mortality And Morbidity ◽  
Amyloid Deposits ◽  
Emerging Therapies ◽  
Immunoglobulin Light Chain Amyloidosis

Abstract Systemic immunoglobulin light chain (LC) amyloidosis (AL) is a potentially fatal disease caused by immunoglobulin LC produced by clonal plasma cells. These LC form both toxic oligomers and amyloid deposits disrupting vital organ function. Despite reduction of LC by chemotherapy, the restoration of organ function is highly variable and often incomplete. Organ damage remains the major source of mortality and morbidity in AL. This review focuses on the challenges posed by emerging therapies that may limit the toxicity of LC and improve organ function by accelerating the resorption of amyloid deposits.

scholarly journals Pressure-Accelerated Dissociation of Amyloid Fibrils in Wild-Type Hen Lysozyme

2012 ◽  
Vol 102 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Buddha R. Shah ◽  
Akihiro Maeno ◽  
Hiroshi Matsuo ◽  
Hideki Tachibana ◽  
Kazuyuki Akasaka
Keyword(s):  
Amyloid Fibrils ◽  
Wild Type

Molecular characterization of three mutations in katG affecting the activity of hydroperoxidase I of Escherichia coli

1990 ◽  
Vol 68 (7-8) ◽  
pp. 1037-1044 ◽  
Author(s):  
Peter C. Loewen ◽  
Jacek Switala ◽  
Mark Smolenski ◽  
Barbara L. Triggs-Raine
Keyword(s):  
Escherichia Coli ◽  
Specific Activity ◽  
Polymerase Chain Reaction Amplification ◽  
Protein A ◽  
Wild Type ◽  
Wild Type Enzyme ◽  
Gene Encoding ◽  
Reaction Amplification ◽  
Mutant Genes

Hydroperoxidase I (HPI) of Escherichia coli is a bifunctional enzyme exhibiting both catalase and peroxidase activities. Mutants lacking appreciable HPI have been generated using nitrosoguanidine and the gene encoding HPI, katG, has been cloned from three of these mutants using either classical probing methods or polymerase chain reaction amplification. The mutant genes were sequenced and the changes from wild-type sequence identified. Two mutants contained G to A changes in the coding strand, resulting in glycine to aspartate changes at residues 119 (katG15) and 314 (katG16) in the deduced amino acid sequence of the protein. A third mutant contained a C to T change resulting in a leucine to phenylalanine change at residue 139 (katG14). The Phe139-, Asp119-, and Asp314-containing mutants exhibited 13, < 1, and 18%, respectively, of the wild-type catalase specific activity and 43, 4, and 45% of the wild-type peroxidase specific activity. All mutant enzymes bound less protoheme IX than the wild-type enzyme. The sensitivities of the mutant enzymes to the inhibitors hydroxylamine, azide, and cyanide and the activators imidazole and Tris were similar to those of the wild-type enzyme. The mutant enzymes were more sensitive to high temperature and to β-mercaptoethanol than the wild-type enzyme. The pH profiles of the mutant catalases were unchanged from the wild-type enzyme.Key words: catalase, hydroperoxidase I, mutants, sequence analysis.

Identification of pilin pools in the membranes of Pseudomonas aeruginosa

1982 ◽  
Vol 152 (2) ◽  
pp. 687-691
Author(s):  
T H Watts ◽  
E A Worobec ◽  
W Paranchych
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Gel Electrophoresis ◽  
Type Strain ◽  
Wild Type Strain ◽  
Polyacrylamide Gel Electrophoresis ◽  
Protein A ◽  
Sodium Dodecyl ◽  
Wild Type ◽  
Outer Membranes

The proteins of purified inner and outer membranes obtained from Pseudomonas aeruginosa strains PAK and PAK/2Pfs were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose, and treated with antiserum raised against pure pili. Bound antipilus antibodies were visualized by reaction with 125I-labeled protein A from Staphylococcus aureus. The results showed that there are pools of pilin in both the inner and outer membranes of P. aeruginosa and that the pool size in the multipiliated strain is comparable with that of the wild-type strain.

scholarly journals Carotenoid-Chlorophyll Interactions in a Photosynthetic Antenna Protein: A Supramolecular QM/MM Approach

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2589 ◽  
Author(s):  
Matthew Guberman-Pfeffer ◽  
José Gascón
Keyword(s):  
Chlorophyll A ◽  
Protein A ◽  
Transition Dipole Moment ◽  
Protein Domain ◽  
Electronic Coupling ◽  
Stoichiometric Ratio ◽  
Wild Type ◽  
Transition Dipole ◽  
Energy Capture ◽  
Photosynthetic Antenna

Multichromophoric interactions control the initial events of energy capture and transfer in the light harvesting peridinin-chlorophyll a protein (PCP) from marine algae dinoflagellates. Due to the van der Waals association of the carotenoid peridinin (Per) with chlorophyll a in a unique 4:1 stoichiometric ratio, supramolecular quantum mechanical/molecular mechanical (QM/MM) calculations are essential to accurately describe structure, spectroscopy, and electronic coupling. We show that, by enabling inter-chromophore electronic coupling, substantial effects arise in the nature of the transition dipole moment and the absorption spectrum. We further hypothesize that inter-protein domain Per-Per interactions are not negligible, and are needed to explain the experimental reconstruction features of the spectrum in wild-type PCP.

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