一种传递力卡德林键的结构,对于内耳机械传导至关重要
Marcos Sotomayor1, Wilhelm A Weihofen, Rachelle Gaudet
1Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|November 9, 2012
概括
揭示了尖端链的分子结构,这对听力和平衡至关重要. 这种cadherin相互作用机制解释了突变如何导致聋,并告知了cadherin生物学.
科学领域:
- 生物物理学的生物物理.
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 内耳中的毛细胞将机械刺激转化为用于听力和平衡的电信号.
- 由protocadherin 15和cadherin 23组成的尖端链接将机械力连接到毛细胞转导通道.
- 这些蛋白质与遗传性聋有关,但它们的分子相互作用是未知的.
研究的目的:
- 为了确定尖端链接内的protocadherin15-cadherin23键的分子结构.
- 了解离子在尖链复合体的稳定性和功能中的作用.
- 阐明与聋相关的突变影响尖端链功能的机制.
主要方法:
- 晶体学 晶体学是指结晶学.
- 分子动力学模拟的模拟.
- 具有约束力的实验
- 生物化学测量 生物化学测量
主要成果:
- 确定了一种新型的卡德林相互作用机制,通过N端卡德林重复形成一个重叠的反平行异构体.
- 模拟表明,尖链键具有适合毛细胞功能的机械强度.
- 复合物在离子被移除后不稳定,突出显示在结构完整性中的作用.
- 阐明了性突变破坏尖端链功能的机制.
结论:
- 这项研究揭示了尖端链接功能在感官传导中的分子基础.
- 发现了一种新的卡德林相互作用机制,对卡德林生物学的影响.
- 这些发现为遗传性聋的分子病因提供了洞察力.
相关概念视频
Structure of Cadherins
The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins” is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins...
Catenins
Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Adherens Junctions
Strong contact points between adjacent cells anchor them to each other, forming tissues. Such anchoring junctions are of two types – adherens junctions and desmosomes. Adherens junctions are abundant in tissues such as epithelium and endothelium, forming a continuous zone of adhesion called the adhesion belt. In other tissues, such as heart muscle, they appear as clusters, linking the cells to produce coordinated heart muscle contraction.
Adherens Junctions are Dynamic
The endothelial cells...
Adherens Junctions are Dynamic
The endothelial cells...
Desmosomes
The term desmosome derives from the Greek words "desmo" and "soma" meaning "adhesion bodies." This structure was first observed during the late 1800s and described as small, dense nodules in the epidermis. Desmosomes are button-like structures that help form an interlinked network of intermediate filaments across the cells. These junctions are essential to hold cells together under mechanical stress and to maintain tissue integrity. Desmosomes are multi-protein complexes comprising desmosomal...
Cadherins in Tissue Organization
The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
Cell Sorting During Development
Cell sorting plays an...
Cell Sorting During Development
Cell sorting plays an...
Tension Response at Adherens Junctions
The adherens junctions that anchor cells together are multi-protein complexes that dynamically adapt to mechanical stimuli such as tensile forces and shear stress. Mechanosensory proteins in these junctions can sense such mechanical stimuli and undergo a shift in their conformation, resulting in an altered function — a process called mechanotransduction.
α-Catenin as a Mechanosensory Protein
The α-catenin of adherens junctions is an allosteric protein with three VH (vinculin homology) domains...
α-Catenin as a Mechanosensory Protein
The α-catenin of adherens junctions is an allosteric protein with three VH (vinculin homology) domains...


