• 한국자기공명학회논문지
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• 제26권1호
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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).

• 생명과학회지
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• 제32권9호
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• pp.729-733
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• 2022

수용성 단백질이 비정상적인 불용성 응집(aggregate)으로 전환되면 질환 등 여러 문제를 야기된다. 대장균 트립토판 중합효소 α 소단위체(αTS)는 가장 흔한 구조의 하나인 TIM 배럴 구조를 가지고 있다. 이전의 연구에서 불용성 응집이 일어나는 여러 잔기치환체(Y4C, S33L, P28L, P28S, G44S, D46N, P96L, P96S)를 얻었다. 본 연구에서는 높은 안정성과 도메인 협동성 성질을 보여주는 Y173F가 다른 잔기자리에 치환으로 유도된 응집 형성을 억제할 수 있는 지 여부를 조사했다. 8개 모두에서 억제효과를 보여 주었다. 단백질 분리가 가능한 P28L αTS를 분석한 결과, 이차구조함량의 감소, 안정성 감소, 소수성표면 증가 등의 구조변화특성을 보여주었다. Y173F가 첨가된 P28L/Y173F αTS은 야생형과 비슷한 구조로 회복되었다. 본 연구는 소수성 코아에 위치하는 Tyr¹⁷³ 잔기처럼 응집을 유도하는 여러 다른 잔기 자리를 보편적으로 억제하는 잔기가 존재할 수 있음을 시사해 준다.

• BMB Reports
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• 제50권7호
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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.

• EDISON SW 활용 경진대회 논문집
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• 제3회(2014년)
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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.