人类γ-分泌酶的基质识别和分离的分子机制
Xuefei Guo1, Haotian Li1, Chuangye Yan1
1Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Key Laboratory for Protein Sciences of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
概括
这项研究揭示了γ-分泌酶处理粉样前体蛋白C终端片段 (APP-C99) 的原子结构及其裂变产物. 这些发现阐明了粉样β生成的阶段性机制.
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 粉样蛋白前体 (APP) 通过γ-分泌酶生成粉样蛋白β (Aβ) ,这与阿尔茨海默病有关.
- 具有99个残留的APP C终端片段 (APP-C99) 是γ-分泌酶的关键基质,产生各种长度的Aβ.
- 顺序性APP-C99裂变的精确机制仍然不完全理解.
研究的目的:
- 确定与APP-C99结合的人类γ-分泌酶及其裂变产物 (Aβ49,Aβ46,Aβ43) 的原子结构.
- 阐明由γ-分泌酶导致APP-C99连续分裂的阶段性机制.
主要方法:
- 通过X射线结晶学检测原子结构.
- 用于分析基质加工的生物化学测试.
主要成果:
- 原子结构显示了保留的基质特征:一个跨膜α-螺旋体,一个链接体和与Presenilin 1 (PS1) 相互作用的β-链.
- 蛋白质分解裂变发生在基 β 链旁边.
- 每个裂变事件都涉及α-螺旋解和转位,随后形成新的β-链.
结论:
- 确定的结构为γ-分泌酶裂变的顺序性,三余步大小提供了机制性的解释.
- 这种机制可能适用于处理其他γ-分泌酶基质.
- 了解这一过程对于向γ-分泌酶活性的治疗策略至关重要.
相关概念视频
Caspases
12.4K
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
12.4K
The Proteasome
8.6K
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
8.6K
The Proteasome Structure
735
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
The proteasome is an...
735
Overview of Secretory Vesicles
8.5K
Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
8.5K
Enzymes
81.4K
Inside living organisms, enzymes act as catalysts for many biochemical reactions involved in cellular metabolism. The role of enzymes is to reduce the activation energies of biochemical reactions by forming complexes with its substrates. The lowering of activation energies favor an increase in the rates of biochemical reactions.
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
81.4K
ATP Synthase: Mechanism
14.5K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.5K


