DNAJB8的寡合化是由一种富含芳香的基因介导的,这种基因对基质活动是不可或缺的
Bryan D Ryder1, Elizaveta Ustyantseva2, David R Boyer3
1Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Structure (London, England : 1993)
|March 20, 2024
概括
J-域蛋白 (JDP) 维护蛋白质组的健康. 研究人员确定了一个DNAJB8动机驱动JDP自组装,揭示了组装和基质活动在蛋白质折叠中的不同角色.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- J-域蛋白 (JDPs) 是蛋白质组恒温的关键分子陪伴者.
- 包括DNAJB8在内的寡头JDPs,由于域名无序,构成结构性特征挑战,阻碍了对其功能的理解.
- 在蛋白质折叠中JDP寡合化的生物学意义尚不清楚.
研究的目的:
- 阐明DNAJB8寡合化的结构基础.
- 调查特定图案在JDP自组装和功能中的作用.
- 了解DNAJB8组装如何影响其与错误折叠的蛋白质和聚合的相互作用.
主要方法:
- 在DNAJB8中负责通过π-π堆叠自组装的芳香基因的识别和结构确定 (X射线晶体学).
- 位点定向的突变发生,以破坏已识别的动机.
- 在体外和细胞测试中评估DNAJB8的寡合化,与错误折叠的tau种子结合,以及蛋白质聚合的减少.
主要成果:
- 在DNAJB8中发现了一个短的芳香基因,它是通过π-π堆叠自我组装的驱动因素,并确定了它的结构.
- 这种基因中的突变在体外和细胞内都废除了DNAJB8的寡合化.
- 非组装DNAJB8变体对错误折叠的种子表现出增强的特异性,并保持其减少蛋白质聚合的能力.
结论:
- 该研究确定了控制DNAJB8寡合化的关键动机,为该过程提供了结构性见解.
- 破坏DNAJB8组装导致对错误折叠的种子的结合增强,并保留了伴侣活动.
- 提出了一种新型模型,在JDP低复杂性域内,不同的序列介于组装和基质参与,为陪伴机制提供了新的视角.
相关概念视频
Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
Cooperative Allosteric Transitions
7.9K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.9K
Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
Nucleophilic Aromatic Substitution: Elimination–Addition
4.0K
Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is...
4.0K
Criteria for Aromaticity and the Hückel 4n + 2 Rule
10.5K
Like benzene, cyclobutadiene and cyclooctatetraene are cyclic compounds with alternate single and double bonds. However, their chemical behavior differs from benzene, as they are unstable and not aromatic. So, what are the structural characteristics of unsaturated compounds categorized as aromatic?
For the first time, Eric Hückel, a German chemical physicist, derived a set of structural features for a compound to be classified as aromatic. This is now known as...
For the first time, Eric Hückel, a German chemical physicist, derived a set of structural features for a compound to be classified as aromatic. This is now known as...
10.5K


