A stoichiometric complex of neurexins and dystroglycan in brain.
A stoichiometric complex of neurexins and dystroglycan in brain.
复制标题
神经毒素和脑部多糖蛋白的化学计量复合物。
DOI：
10.1083/jcb.200105003
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发表时间：
2001-07-23
影响因子：
7.8
通讯作者：
Sudhof, T C
中科院分区：
文献类型：
--
作者：
Sugita, S;Saito, F;Tang, J;Satz, J;Campbell, K;Sudhof, T C
在非神经元细胞中，细胞表面蛋白肌营养不良蛋白聚糖将细胞内细胞骨架（通过肌营养不良蛋白或肌营养不良蛋白）连接到细胞外基质（通过层粘连蛋白，聚集蛋白或串珠蛋白聚糖）。这种联系的损害有助于肌营养不良症的发病机制。在脑中，肌营养不良蛋白聚糖和肌营养不良蛋白在神经元和星形胶质细胞上表达，并且一些肌营养不良症引起认知功能障碍;然而，已知神经元肌营养不良蛋白聚糖的细胞外结合伴侣。细胞外基质的常规组分，如层粘连蛋白、聚集蛋白和串珠蛋白聚糖，在脑中并不丰富，除了在血管周围空间中，所述血管周围空间由星形胶质细胞接触而不是由神经元接触，这表明神经元营养不良蛋白聚糖的其他配体必须存在。我们现在已经鉴定出α-和β-neurexins，多态性神经元特异性细胞表面蛋白，作为神经元肌营养不良蛋白聚糖受体。α-和β-neurexins的细胞外序列主要由层粘连蛋白-neurexin-性激素结合球蛋白（LNS）/层粘连蛋白G结构域组成，这些结构域也存在于层粘连蛋白、聚集蛋白和串珠蛋白聚糖中，它们是肌营养不良蛋白聚糖配体。肌营养不良聚糖以紧密相互作用特异性结合神经毒素的LNS结构域的子集，所述紧密相互作用需要肌营养不良聚糖的糖基化并且通过神经毒素的选择性剪接来调节。神经毒素是兴奋性神经毒素α-latrotoxin的受体;该毒素与肌营养不良蛋白聚糖竞争结合，表明神经毒素上肌营养不良蛋白聚糖和α-latrotoxin的结合位点重叠。我们的数据表明，肌营养不良蛋白聚糖是neurexins的生理配体，neurexins的紧密调控的相互作用可以介导脑细胞之间的细胞粘附。
In nonneuronal cells, the cell surface protein dystroglycan links the intracellular cytoskeleton (via dystrophin or utrophin) to the extracellular matrix (via laminin, agrin, or perlecan). Impairment of this linkage is instrumental in the pathogenesis of muscular dystrophies. In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction; however, no extracellular binding partner for neuronal dystroglycan is known. Regular components of the extracellular matrix, such as laminin, agrin, and perlecan, are not abundant in brain except in the perivascular space that is contacted by astrocytes but not by neurons, suggesting that other ligands for neuronal dystroglycan must exist. We have now identified α- and β-neurexins, polymorphic neuron-specific cell surface proteins, as neuronal dystroglycan receptors. The extracellular sequences of α- and β-neurexins are largely composed of laminin-neurexin–sex hormone–binding globulin (LNS)/laminin G domains, which are also found in laminin, agrin, and perlecan, that are dystroglycan ligands. Dystroglycan binds specifically to a subset of the LNS domains of neurexins in a tight interaction that requires glycosylation of dystroglycan and is regulated by alternative splicing of neurexins. Neurexins are receptors for the excitatory neurotoxin α-latrotoxin; this toxin competes with dystroglycan for binding, suggesting overlapping binding sites on neurexins for dystroglycan and α-latrotoxin. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells.