Prion Domain of Yeast Ure2 Protein Adopts a Completely Disordered Structure: A Solid-Support EPR Study

Ngo, Sam; Chiang, Vicky; Ho, Elaine Lynn‐Ee; Le, Linh-Thy; Guo, Zhefeng

doi:10.1371/journal.pone.0047248

Cited by 13 publications

(11 citation statements)

References 44 publications

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“…The EPR spectra of spin-labeled A␤42 globulomers encode information about the mobility of the spin label at each labeling site. The spin label mobility can be measured using center line width (45) or the ratio of high field and center line amplitude (46). For EPR spectra with multiple components reflecting multiple motional states of the spin label, however, these measurements report only the combined mobility from different spin label states.…”

Section: Resultsmentioning

confidence: 99%

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Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling

Gu¹,

Liu²,

Guo³

2013

Journal of Biological Chemistry

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Oligomerization of the 42-residue peptide Aβ42 plays a key role in the pathogenesis of Alzheimer disease. Despite great academic and medical interest, the structures of these oligomers have not been well characterized. Site-directed spin labeling combined with electron paramagnetic resonance spectroscopy is a powerful approach for studying structurally ill-defined systems, but its application in amyloid oligomer structure study has not been systematically explored. Here we report a comprehensive structural study on a toxic Aβ42 oligomer, called globulomer, using site-directed spin labeling complemented by other techniques. Transmission electron microscopy shows that these oligomers are globular structures with diameters of ∼7-8 nm. Circular dichroism shows primarily β-structures. X-ray powder diffraction suggests a highly ordered intrasheet hydrogen-bonding network and a heterogeneous intersheet packing. Residue-level mobility analysis on spin labels introduced at 14 different positions shows a structured state and a disordered state at all labeling sites. Side chain mobility analysis suggests that structural order increases from N- to C-terminal regions. Intermolecular distance measurements at 14 residue positions suggest that C-terminal residues Gly-29-Val-40 form a tightly packed core with intermolecular distances in a narrow range of 11.5-12.5 Å. These intermolecular distances rule out the existence of fibril-like parallel in-register β-structures and strongly suggest an antiparallel β-sheet arrangement in Aβ42 globulomers.

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Section: Resultsmentioning

confidence: 99%

“…3B). Spin labels in completely unfolded proteins have a correlation time of ϳ0.5 ns (46,47), suggesting that this fast component corresponds to a partly disordered state. The relative population of the fast component is ϳ25% for N-terminal region (residues 1-10) and 10 -15% for most other residues ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling

Gu¹,

Liu²,

Guo³

2013

Journal of Biological Chemistry

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“…122 PrDs of prions that exhibit self assembly and aggregation are found to exist in disordered state and are also predicted to be IDRs/LC domains. [164][165][166] The biophysical nature and structural details of interaction between these domains in vivo remains to be clearly identified. Strikingly although only 1% of human genome contain RNA recognition motif (RRM), 11% of human prion domain containing proteins possess RRM, indicating their enrichment in the subset.…”

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

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“…Interestingly, it has been reported that Q was overrepresented in protein interaction domains [37]. It was recently reported that the Ure2p prion and other Q/N-rich yeast prion proteins, which were completely disordered, were driven to format amyloid primarily by intermolecular interactions [38]. Meanwhile, as shown in Figure 3(b), for the 21-length peptides, PSSM conservation scores at sites 8–15 played the most important role.…”

Section: Resultsmentioning

confidence: 94%

A Novel Method of Predicting Protein Disordered Regions Based on Sequence Features

Zhao

Jiang

Huang

et al. 2013

BioMed Research International

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With a large number of disordered proteins and their important functions discovered, it is highly desired to develop effective methods to computationally predict protein disordered regions. In this study, based on Random Forest (RF), Maximum Relevancy Minimum Redundancy (mRMR), and Incremental Feature Selection (IFS), we developed a new method to predict disordered regions in proteins. The mRMR criterion was used to rank the importance of all candidate features. Finally, top 128 features were selected from the ranked feature list to build the optimal model, including 92 Position Specific Scoring Matrix (PSSM) conservation score features and 36 secondary structure features. As a result, Matthews correlation coefficient (MCC) of 0.3895 was achieved on the training set by 10-fold cross-validation. On the basis of predicting results for each query sequence by using the method, we used the scanning and modification strategy to improve the performance. The accuracy (ACC) and MCC were increased by 4% and almost 0.2%, respectively, compared with other three popular predictors: DISOPRED, DISOclust, and OnD-CRF. The selected features may shed some light on the understanding of the formation mechanism of disordered structures, providing guidelines for experimental validation.

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Prion Domain of Yeast Ure2 Protein Adopts a Completely Disordered Structure: A Solid-Support EPR Study

Cited by 13 publications

References 44 publications

Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling

Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

A Novel Method of Predicting Protein Disordered Regions Based on Sequence Features

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