PrP interactions with nucleic acids and glycosaminoglycans in function and disease

Jerson, L. Silva

doi:10.2741/3611

Cited by 30 publications

(25 citation statements)

References 161 publications

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“…Over the last decade evidence has been accumulating in support of the hypothesis that various non-protein macromole-cules are involved in prion formation and propagation (43,44). Of the numerous possible adjuvants, nucleic acids have successfully been identified as the interaction partners of many disease-related proteins (24,(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Kovachev

Banerjee

Rangel

et al. 2017

Journal of Biological Chemistry

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Inactivation of the tumor suppressor protein p53 by mutagenesis, chemical modification, protein-protein interaction, or aggregation has been associated with different human cancers. Although DNA is the typical substrate of p53, numerous studies have reported p53 interactions with RNA. Here, we have examined the effects of RNA of varied sequence, length, and origin on the mechanism of aggregation of the core domain of p53 (p53C) using light scattering, intrinsic fluorescence, transmission electron microscopy, thioflavin-T binding, seeding, and immunoblot assays. Our results are the first to demonstrate that RNA can modulate the aggregation of p53C and full-length p53. We found bimodal behavior of RNA in p53C aggregation. A low RNA:protein ratio (∼1:50) facilitates the accumulation of large amorphous aggregates of p53C. By contrast, at a high RNA:protein ratio (≥1:8), the amorphous aggregation of p53C is clearly suppressed. Instead, amyloid p53C oligomers are formed that can act as seeds nucleating aggregation of p53C. We propose that structured RNAs prevent p53C aggregation through surface interaction and play a significant role in the regulation of the tumor suppressor protein.

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Section: Discussionmentioning

confidence: 99%

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Kovachev

Banerjee

Rangel

et al. 2017

Journal of Biological Chemistry

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“…Conflicting results have been reported of the interaction of heparin and heparan sulfate with PrP C (reviewed in [164]). Certain studies suggested that these GAGs prevent PrP aggregation and conformational conversion [169,170].…”

Section: Interaction Of Glycosaminoglycans With the Prion Proteinmentioning

confidence: 98%

“…Glycosaminoglycans have been implicated in the pathogenesis of prion diseases [159][160][161][162][163][164]. It was shown that GAGs bind the prion protein both when the latter is anchored at the plasma membrane, as well as in a nonglycosylated form in vitro [165,166], and it was proposed that GAGs in general interact with PrP C through its N-terminal domain [166,167].…”

Section: Interaction Of Glycosaminoglycans With the Prion Proteinmentioning

confidence: 99%

Allosteric function and dysfunction of the prion protein

Linden¹,

Cordeiro

Lima

2011

Cell. Mol. Life Sci.

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Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases associated with progressive oligo- and multimerization of the prion protein (PrP(C)), its conformational conversion, aggregation and precipitation. We recently proposed that PrP(C) serves as a cell surface scaffold protein for a variety of signaling modules, the effects of which translate into wide-range functional consequences. Here we review evidence for allosteric functions of PrP(C), which constitute a common property of scaffold proteins. The available data suggest that allosteric effects among PrP(C) and its partners are involved in the assembly of multi-component signaling modules at the cell surface, impose upon both physiological and pathological conformational responses of PrP(C), and that allosteric dysfunction of PrP(C) has the potential to entail progressive signal corruption. These properties may be germane both to physiological roles of PrP(C), as well as to the pathogenesis of the TSEs and other degenerative/non-communicable diseases.

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“…Protein misfolding occurs due to gene mutations, which lead to an inability of the produced protein to correctly fold, malfunction of the protein trafficking machinery and abnormal protein interaction with different molecular partners in the cellular milieu [10,44,46,47]. The aggregates can be formed intracellularly, as is the case with α-synuclein (Parkinson's disease), SOD (superoxide dismutase) (in ALS) and huntingtin (Huntington's disease) [43] or extracellularly, as is the case in prion diseases [48,49], Type 2 diabetes [due to the aggregation of the IAPP (islet amyloid polypeptide)] [50,51] and AD [43].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, such DNA sequences could be exploited as a new approach to cancer therapy in the near future. The use of small aptameric nucleic acids and other polyanions has been proposed to modulate aggregation of the prion protein [47,62,84]. On the other hand, p53 has been previously described to form long fibrillar segments complexed with DNA [85].…”

Section: Introductionmentioning

confidence: 99%

Expanding the prion concept to cancer biology: dominant-negative effect of aggregates of mutant p53 tumour suppressor

et al. 2013

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p53 is a key protein that participates in cell-cycle control, and its malfunction can lead to cancer. This tumour suppressor protein has three main domains; the N-terminal transactivation domain, the CTD (C-terminal domain) and the core domain (p53C) that constitutes the sequence-specific DBD (DNA-binding region). Most p53 mutations related to cancer development are found in the DBD. Aggregation of p53 into amyloid oligomers and fibrils has been shown. Moreover, amyloid aggregates of both the mutant and WT (wild-type) forms of p53 were detected in tumour tissues. We propose that if p53 aggregation occurred, it would be a crucial aspect of cancer development, as p53 would lose its WT functions in an aggregated state. Mutant p53 can also exert a dominant-negative regulatory effect on WT p53. Herein, we discuss the dominant-negative effect in light of p53 aggregation and the fact that amyloid-like mutant p53 can convert WT p53 into more aggregated species, leading into gain of function in addition to the loss of tumour suppressor function. In summary, the results obtained in the last decade indicate that cancer may have characteristics in common with amyloidogenic and prion diseases.

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PrP interactions with nucleic acids and glycosaminoglycans in function and disease

Cited by 30 publications

References 161 publications

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain

Allosteric function and dysfunction of the prion protein

Expanding the prion concept to cancer biology: dominant-negative effect of aggregates of mutant p53 tumour suppressor

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