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1

The specificity of intracellular protein aggregation

100%

Milewski M. I., Mickle J. E., Cutting G. R.

Cellular and Molecular Biology Letters

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2002

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tom 07

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nr Suppl.

2

The CFTR-derived peptides as a model of sequence-specific protein aggregation

86%

Bak D., Cutting G. R., Milewski M.

Cellular and Molecular Biology Letters

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2007

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tom 12

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nr 3

Protein aggregation is a hallmark of a growing group of pathologies known as conformational diseases. Although many native or mutated proteins are able to form aggregates, the exact amino acid sequences involved in the process of aggregation are known only in a few cases. Hence, there is a need for different model systems to expand our knowledge in this area. The so-called ag region was previously found to cause the aggregation of the C-terminal fragment of the cystic fibrosis transmembrane conductance regulator (CFTR). To investigate whether this specific amino acid sequence is able to induce protein aggregation irrespective of the amino acid context, we altered its position within the CFTR-derived C-terminal peptide and analyzed the localization of such modified peptides in transfected mammalian cells. Insertion of the ag region into a different amino acid background affected not only the overall level of intracellular protein aggregation, but also the morphology and subcellular localization of aggregates, suggesting that sequences other than the ag region can substantially influence the peptide’s behavior. Also, the introduction of a short dipeptide (His-Arg) motif, a crucial component of the ag region, into different locations within the C-terminus of CFTR lead to changes in the aggregation pattern that were less striking, although still statistically significant. Thus, our results indicate that even subtle alterations within the aggregating peptide can affect many different aspects of the aggregation process.

3

Escherichia coli small heat shock proteins IbpA-B enhance activity of enzymes sequestered in inclusion bodies

86%

Kuczynska-Wisnik D., Zurawa-Janicka D., Narkiewicz J., Kwiatkowska J., Lipinska B., Laskowska E.

Acta Biochimica Polonica

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2004

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tom 51

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nr 4

Escherichia coli small heat shock proteins, IbpA/B, function as molecular chape- rones and protect misfolded proteins against irreversible aggregation. IbpA/B are induced during overproduction of recombinant proteins and bind to inclusion bodies in E. coli cells. We investigated the effect of AibpA/B mutation on formation of inclusion bodies and biological activity of enzymes sequestered in the aggregates in E. coli cells. Using three different recombinant proteins: Cro-ß-galactosidase, ß-lactamase and rat rHtrA1 we demonstrated that deletion of the ibpA/B operon did not affect the level of produced inclusion bodies. However, in aggregates containing IbpA/B a higher enzymatic activity was detected than in the IbpA/B-deficient inclusion bodies. These results confirm that IbpA/B protect misfolded proteins from inactivation in vivo.

4

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

72%

Bialy L. P., Fayet J., Wilczynski G. M., Mlynarczuk-Bialy I.

Folia Histochemica et Cytobiologica

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2018

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tom 56

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nr 4

5

Neurodegenerative aspects of protein aggregation

72%

Trzesniewska K., Brzyska M., Elbaum D.

Acta Neurobiologiae Experimentalis

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2004

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tom 64

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nr 1

6

3D domain swapping, protein oligomerization, and amyloid formation

72%

Jaskolski M.

Acta Biochimica Polonica

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2001

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tom 48

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nr 4

In 3D domain swapping, first described by Eisenberg, a structural element of a monomeric protein is replaced by the same element from another subunit. This process requires partial unfolding of the closed monomers that is then followed by adhesion and reconstruction of the original fold but from elements contributed by different subunits. If the interactions are reciprocal, a closed-ended dimer will be formed, but the same phenomenon has been suggested as a mechanism for the formation of open-ended polymers as well, such as those believed to exist in amyloid fibrils. There has been a rapid progress in the study of 3D domain swapping. Oligomers higher than dimers have been found, the monomer-dimer equilibrium could be controlled by mutations in the hinge element of the chain, a single protein has been shown to form more than one domain-swapped structure, and recently, the possibility of simultaneous exchange of two structural domains by a single molecule has been demonstrated. This last discovery has an important bearing on the possibility that 3D domain swapping might be indeed an amyloidogenic mechanism. Along the same lines is the discovery that a protein of proven amyloidogenic properties, human cystatin C, is capable of 3D domain swapping that leads to oligomerization. The structure of domain- swapped human cystatin C dimers explains why a naturally occurring mutant of this protein has a much higher propensity for aggregation, and also suggests how this same mechanism of 3D domain swapping could lead to an open-ended polymer that would be consistent with the cross-β structure, which is believed to be at the heart of the molecular architecture of amyloid fibrils.

7

Modulation of physiological and pathological activities of lysozyme by biological membranes

58%

Trusova V.

Cellular and Molecular Biology Letters

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2012

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tom 17

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nr 3

The molecular details of interactions between lipid membranes and lysozyme (Lz), a small polycationic protein with a wide range of biological activities, have long been the focus of numerous studies. The biological consequences of this process are considered to embrace at least two aspects: i) correlation between antimicrobial and membranotropic properties of this protein, and ii) lipid-mediated Lz amyloidogenesis. The mechanisms underlying the lipid-assisted protein fibrillogenesis and membrane disruption exerted by Lz in bacterial cells are believed to be similar. The present investigation was undertaken to gain further insight into Lz-lipid interactions and explore the routes by which Lz exerts its antimicrobial and amyloidogenic actions. Binding and Förster resonance energy transfer studies revealed that upon increasing the content of anionic lipids in lipid vesicles, Lz forms aggregates in a membrane environment. Total internal reflection fluorescence microscopy and pyrene excimerization reaction were employed to study the effect of Lz on the structural and dynamic properties of lipid bilayers. It was found that Lz induces lipid demixing and reduction of bilayer free volume, the magnitude of this effect being much more pronounced for oligomeric protein.

8

Role of Escherichia coli heat shock proteins IbpA and IbpB in protection of alcohol dehydrogenase AdhE against heat inactivation in the presence of oxygen

58%

Matuszewska E., Kwiatkowska J., Ratajczak E., Kuczynska-Wisnik D., Laskowska E.

Acta Biochimica Polonica

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2009

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tom 56

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nr 1

55-61

Escherichia coli small heat shock proteins IbpA and IbpB are molecular chaperones that bind denatured proteins and facilitate their subsequent refolding by the ATP-dependent chaperones DnaK/DnaJ/GrpE and ClpB. In vivo, the lack of IbpA and IbpB proteins results in increased protein aggregation under severe heat stress or delayed removal of aggregated proteins at recovery temperatures. In this report we followed the appearance and removal of aggregated alcohol dehydrogenase, AdhE, in E. coli submitted to heat stress in the presence of oxygen. During prolonged incubation of cells at 50oC, when AdhE was progressively inactivated, we initially observed aggregation of AdhE and thereafter removal of aggregated AdhE. In contrast to previous studies, the lack of IbpA and IbpB did not influence the formation and removal of AdhE aggregates. However, in ΔibpAB cells AdhE was inactivated and oxidized faster than in wild type strain. Our results demonstrate that IbpA and IbpB protected AdhE against thermal and oxidative inactivation, providing that the enzyme remained soluble. IbpA and IbpB were dispensable for the processing of irreversibly damaged and aggregated AdhE.

9

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3D domain swapping – implications for conformational disorders and ways of control

58%

Jaskolski M.

BioTechnologia. Journal of Biotechnology Computational Biology and Bionanotechnology

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2011

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tom 92

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nr 1

10

Dynein c1h1, dynactin and syntaphilin expression in brain areas related to neurodegenerative diseases following exposure to rotenone

58%

Chaves R. S., Melo T. Q., D'Unhao A. M., Farizatto K. L. G., Ferrari M. F. R.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 4

Neurodegeneration is often accompanied by protein inclusions which may interfere with cell physiology. On the other hand, alteration in intracellular trafficking may precede impairment of neurotransmission and therefore trigger cell death. In view of this, it is hypothesized that changes in mitochondrial traffic may occur before neurodegeneration triggered by rotenone exposure and could favor this process. The effects of low concentrations of rotenone on the expression of dynein clhl, dynactin and syntaphilin, which are proteins related to mitochondria transport and anchoring, were evaluated in cell cultures of substantia nigra, locus coeruleus and hippocampus as well as in these same brain areas in Lewis aged rats. The results indicate that low concentrations of rotenone decrease dynein clhl protein levels in cell cultures and brain areas of aged rats. Dynactin is decreased after exposure to 0.1 and 0.3 nM of rotenone, and increased after exposure to 0.5 nM of rotenone in cell cultures. Aged rats present increased dynactin expression. Syntaphilin expression decreased in vitro and increased in vivo after rotenone exposure. These findings suggest that changes in protein expression related to mitochondrial retrograde transport and anchoring occur before neurodegeneration induced by rotenone exposure, which may be a primary factor to trigger neurodegenerative mechanisms.

11

Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease

58%

Kirkitadze M. D., Kowalska A.

Acta Biochimica Polonica

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2005

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tom 52

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nr 2

The deposition of aggregated amyloid β-protein (Aβ) in the human brain is a major lesion in Alzheimer’s disease (AD). The process of Aβ fibril formation is associated with a cascade of neuropathogenic events that induces brain neurodegeneration leading to the cognitive and behavioral decline characteristic of AD. Although a detailed knowledge of Aβ assembly is crucial for the development of new therapeutic approaches, our understanding of the molecular mechanisms underlying the initiation of Aβ fibril formation remains very incomplete. The genetic defects responsible for familial AD influence fibrillogenesis. In a majority of familial cases determined by amyloid precursor protein (APP) and presenilin (PS) mutations, a significant overproduction of Aβ and an increase in the Aβ42/Aβ40 ratio are observed. Recently, it was shown that the two main alloforms of Aβ have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies demonstrated that Aβ42 monomers, but not Aβ40, form initial and minimal structures (pentamer/hexamer units called paranuclei) that can oligomerize to larger forms. It is now apparent that Aβ oligomers and protofibrils are more neurotoxic than mature Aβ fibrils or amyloid plaques. The neurotoxicity of the prefibrillar aggregates appears to result from their ability to impair fundamental cellular processes by interacting with the cellular membrane, causing oxidative stress and increasing free Ca2+ that eventually lead to apoptotic cell death.

Ograniczanie wyników

The specificity of intracellular protein aggregation

The CFTR-derived peptides as a model of sequence-specific protein aggregation

Escherichia coli small heat shock proteins IbpA-B enhance activity of enzymes sequestered in inclusion bodies

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

Neurodegenerative aspects of protein aggregation

3D domain swapping, protein oligomerization, and amyloid formation

Modulation of physiological and pathological activities of lysozyme by biological membranes

Role of Escherichia coli heat shock proteins IbpA and IbpB in protection of alcohol dehydrogenase AdhE against heat inactivation in the presence of oxygen

3D domain swapping – implications for conformational disorders and ways of control

Dynein c1h1, dynactin and syntaphilin expression in brain areas related to neurodegenerative diseases following exposure to rotenone

Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease