素A11的proline丰富域的ALS变体损害了其S100A6-介导的纤维素溶解
Aman Shihora1, Ruben D Elias1, John A Hammond2
1Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.
ACS chemical neuroscience
|July 11, 2023
概括
附件A11中的突变.
科学领域:
- 生物化学和分子生物学
- 神经科学是一个神经科学.
- 蛋白质错折叠疾病 蛋白质错折叠疾病
背景情况:
- 附件A11 (A11) 的富含proline域 (PRD) 中的突变与肌缩性侧面硬化症 (ALS) 有关.
- 这些突变导致神经元A11包容的形成,但潜在的机制仍然不清楚.
- 附件A11与S100A6相互作用,这种蛋白质在ALS患者中被发现过度表达.
研究的目的:
- 为了研究ALS相关的A11-PRD变体的体外行为.
- 阐明A11聚合的机制及其通过S100A6.6的调制.
- 了解ALS相关突变如何影响A11纤维素动态和溶解.
主要方法:
- 再组合蛋白的表达和净化.
- 在体外液体液相分离和粉样纤维素形成试验.
- 纤维细胞形成和溶解动力学的生物物理特征.
- 使用结合试验分析蛋白质与蛋白质相互作用.
主要成果:
- 重组A11-PRD及其ALS变体形成类似液体的凝结物,成熟为粉样纤维.
- S100A6促进了A11粉样纤维的溶解.
- 由于纤维素与单体的交换速度较慢,ALS变种的纤维化率较慢,S100A6介导纤维素溶解显著降低.
- 尽管聚合速度较慢,但ALS变体更容易发生持续的聚合.
结论:
- 在A11-PRD中与ALS相关的突变促进了粉样纤维的形成.
- 更慢的纤维溶解动力学,而不是改变S100A6的结合亲和力,解释了ALS变体的聚合倾向的增加.
- 这些发现提供了对ALS病变发生过程中的A11聚合的机制性见解.
相关概念视频
Fibril-associated Collagen
2.6K
Fibril-associated collagens are a type of collagens present in the extracellular matrix with interrupted triple helices or FACIT (Fibril-associated collagens interrupted triple-helices). FACIT help connect and attach the collagen fibrils with each other as well as with other proteins of the extracellular matrix.
For example, the type II collagen fibrils in cartilage have covalently bound type IX fibril-associated collagens at regular intervals. Other types of fibril-associated collagens are...
For example, the type II collagen fibrils in cartilage have covalently bound type IX fibril-associated collagens at regular intervals. Other types of fibril-associated collagens are...
2.6K
Actin Filament Depolymerization
3.1K
Actin filaments (F-actin) are composed of actin subunits. The dissociation of actin monomers can occur from either end of F-actin. The rate of dissociation is faster from the minus-end or the pointed end, where the actin subunits exist with a bound ADP, together known as ADP-actin. The depolymerization of F-actin is aided by proteins, including the actin-depolymerizing factor (ADF) and cofilin family of proteins, gelsolin, and glia maturation factor (GMF).
In F-actin, the ADF/cofilin proteins...
In F-actin, the ADF/cofilin proteins...
3.1K
Intracellular Signaling Affects Focal Adhesions
2.7K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
2.7K
Amyloid Fibrils
9.6K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.6K
Clot Retraction and Fibrinolysis
6.5K
After a fibrin clot is formed, the next step is clot retraction, a vital process facilitated by platelet contractile proteins, such as actin and myosin. These proteins pull the fibrin strands closer together and condense the clot. This action reduces the size of the clot, creating a smaller, denser structure that effectively seals off the damaged vessel. Clot retraction consolidates the clot and helps with wound healing by bringing the edges of the damaged blood vessel closer together.
6.5K
Cytoskeletal Accessory Proteins
3.1K
The cytoskeleton is an essential cell component that plays several structural and functional roles. However, the filaments that make up the cytoskeleton cannot function independently and depend on the accessory or ancillary proteins to effectively carry out their function. Accessory proteins associate with cytoskeletal filaments and their monomers, aiding filament formation and function. They also help in the cross-communication among cytoskeletal filaments. Cytoskeletal accessory proteins are...
3.1K


