整合素中的全ostery 的结构基础和与纤维原模拟疗法的结合
Tsan Xiao1, Junichi Takagi, Barry S Coller
1The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature
|September 21, 2004
概括
集成蛋白是细胞粘附受体的关键. 晶体结构揭示了这些受体如何改变形状并与纤维素素等连接体结合,从而影响细胞相互作用.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 细胞生物学 细胞生物学
背景情况:
- 整合素是关键的细胞表面受体,参与细胞粘附和信号传导.
- 它们是由α和β子单元组成的异构分子蛋白质,跨越细胞膜.
- 整体蛋白通过膜双向传递构造变化,影响细胞行为.
研究的目的:
- 为了阐明整合因子子域中的全调节的原子基础.
- 了解纤维原模拟疗法如何与血小板整合素α{\displaystyle \alpha }{\displaystyle \alpha }{\displaystyle \alpha }{\displaystyle \beta }{\displaystyle \beta }{\displaystyle \beta }{\displaystyle \alpha }{\displaystyle \beta }{\displaystyle \beta }}结合在一起.
- 定义底层的整合素构造变化和连接体亲和度调节的结构机制.
主要方法:
- 采用X射线晶体学来确定整合素ectodomains的原子结构.
- 结构分析的重点是β3I域,混合域和plexin/semaphorin/integrin (PSI) 域.
- 通过比较不同的整合素构造来理解全性传播.
主要成果:
- 晶体结构揭示了整合素ectodomain中的全调节的原子细节.
- 贝塔3I域中的体变化会影响金属结合点,循环和螺旋.
- 阿尔法7螺旋体的活塞式移位重新定向了β3I和混合领域,导致腿部延伸和高亲和度头部定位.
结论:
- 这项研究提供了对整合素性调节的详细原子理解.
- 结构洞察力解释了如何通过形状变化调节连接体结合亲和力.
- 这些发现对于理解整合素功能和开发向治疗,如纤维素仿真药物相关.
相关概念视频
01:58Cooperative Allosteric Transitions
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...
01:58Cooperative Allosteric Transitions
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...
01:25Fibronectins Connect Cells with ECM
Fibronectin is an adhesive glycoprotein present in the extracellular matrix of embryogenic and adult tissue. These molecules primarily aid in regulating cell motility and attachment. A fibronectin molecule is composed of two identical polypeptide chains attached to each other by a pair of disulfide bonds at the C-terminal.
Both proteoglycans and collagen are attached to fibronectin proteins, which, in turn, are attached to integrin proteins. These integrin proteins interact with transmembrane...
Both proteoglycans and collagen are attached to fibronectin proteins, which, in turn, are attached to integrin proteins. These integrin proteins interact with transmembrane...
01:10Integrins
Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
01:15Activation of Integrins
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
01:17Intracellular Signaling Affects Focal Adhesions
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...