• Journal of the Korean Magnetic Resonance Society
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• v.26 no.1
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• pp.17-20
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• 2022

High-pressure (HP) NMR is a versatile tool to investigate diverse features of proteins. This technique has been particularly powerful to elucidate structural dynamics that only populates sufficiently in a pressurized condition. Amyloidogenic proteins, which are prone to aggregate and form amyloid fibrils, often maintains highly dynamic states in its native or aggregation-prone states, and HP NMR contributed much to advance our understandings of the dynamic behaviors of amyloidogenic proteins and the molecular mechanisms of their aggregation. In this mini review, we therefore summarize recent HP NMR studies on amyloid-beta (Aβ), the representative amyloidogenic intrinsically disordered protein (IDP).

• Journal of Life Science
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• v.32 no.9
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• pp.729-733
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• 2022

Aggregation of normally soluble proteins can cause disease-related problems. Tryptophan synthase α-subunit (αTS) in E. coli adopts one of most popular structural scaffolds, the TIM barrel fold. Previous mutagenesis of the αTS gene resulted in many aggregation-prone mutant proteins. Here, Y173F (Tyr at residue 173 to Phe) substitution, which imparts increased stability, was tested for its ability to suppress aggregation of aggregation-prone mutant proteins (Y4C, S33L, P28L, P28S, G44S, D46N, P96L, and P96S). Aggregation was suppressed in all eight severe aggregate-forming mutants (all differing in their mutation positions), by the Y173F replacement. P28L αTS, which was available in pure form, was further analyzed and showed reduced secondary structure content, lower stability, and a looser structure with more exposed hydrophobic surface compared to the wild type protein. A double mutant P28L/Y173F protein showed almost no indication of these changes compared to the wild type protein. We hypothesized that Tyr at position 173 in αTS is positioned at the hydrophobic core and may serve to suppress the aggregation of this protein caused by other residues. Important residue (s) could be working widely in the prevention/suppression of protein aggregation.

• BMB Reports
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• v.50 no.7
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• pp.345-354
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• 2017

Autophagy, a catabolic process necessary for the maintenance of intracellular homeostasis, has recently been the focus of numerous human diseases and conditions, such as aging, cancer, development, immunity, longevity, and neurodegeneration. However, the continued presence of autophagy is essential for cell survival and dysfunctional autophagy is thought to speed up the progression of neurodegeneration. The actual molecular mechanism behind the progression of dysfunctional autophagy is not yet fully understood. Emerging evidence suggests that basal autophagy is necessary for the removal of misfolded, aggregated proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid ${\beta}$ peptide and ${\alpha}-synuclein$ protein aggregation, as seen in patients with Alzheimer's disease and Parkinson's disease, respectively. Even though autophagy could impact several facets of human biology and disease, it generally functions as a clearance for toxic proteins in the brain, which contributes novel insight into the pathophysiological understanding of neurodegenerative disorders. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimuli are essential in the clearance of amyloid ${\beta}$ and ${\alpha}-synuclein$ deposits. Therefore, this review briefly deliberates on the recent implications of autophagy in neurodegenerative disorder control, and emphasizes the opportunities and potential therapeutic application of applied autophagy.

• Proceeding of EDISON Challenge
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• 2014.03a
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• pp.237-249
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• 2014

Deposition of amyloid-${\beta}$ ($A{\beta}$) proteins is the conventional pathological hallmark of Alzheimer's disease (AD). The $A{\beta}$ protein formed from the amyloid precursor protein is predominated by the 40 residue protein ($A{\beta}40$) and by the 42 residue protein ($A{\beta}42$). While $A{\beta}40$ and $A{\beta}42$ differ in only two amino acid residues at the C-terminal end, $A{\beta}42$ is much more prone to aggregate and exhibits more neurotoxicity than $A{\beta}40$. Here, we investigate the molecular origin of the difference in the aggregation propensity of these two proteins by performing fully atomistic, explicit-water molecular dynamics simulations. Then, it is followed by the solvation thermodynamic analysis based on the integral-equation theory of liquids. We find that $A{\beta}42$ displays higher tendency to adopt ${\beta}$-sheet conformations than $A{\beta}40$, which would consequently facilitate the conversion to the ${\beta}$-sheet rich fibril structure. Furthermore, the solvation thermodynamic analysis on the simulated protein conformations indicates that $A{\beta}42$ is more hydrophobic than $A{\beta}40$, implying that the surrounding water imparts a larger thermodynamic driving force for the self-assembly of $A{\beta}42$. Taken together, our results provide structural and thermodynamic grounds on why $A{\beta}42$ is more aggregation-prone than $A{\beta}40$ in aqueous environments.