DESMOCOLLINS AND CELLULAR ADHESION

该项目的长期目标是描述 桥粒柯林斯在细胞-细胞粘附中的作用。 桥粒柯林斯是主要的糖蛋白 桥粒的组成部分，以及粘附破坏的目标 严重水疱患者血清中存在的抗体 寻常性天疱疮 在结构上，它们形成了一个独特的子集， 钙粘蛋白是细胞间粘附和识别分子的一个家族。 桥粒柯林斯作为许多组织特异性同种型存在， 选择性剪接 这些异构体的确切作用尚不清楚。 据推测，它们是必不可少的粘附机制， 桥粒，并可能在细胞识别、细胞骨架 结合以及初始细胞-细胞接触的接收和转导 信号. 桥粒胶蛋白亚型在成人组织中的分布， 在胚胎发育期间，将通过免疫化学和PCR进行检查 确定表达模式是否兼容的技术 在形态发生中起作用。 异构体与 其他连接组分和激酶将被检查，通过 共沉淀和体外结合试验，以确定它们是否 在信号转导和/或细胞骨架结合中起作用。 类似 技术将被用来定义是否他们的关联在平面 是同型的还是异型的。 介导这些基因的序列 并调节这些分子的结合亲和力将被研究， 比较野生型和重组桥粒柯林斯的能力 支持细胞-细胞粘附和粘附破坏能力 抗体干扰这一过程。 控制着 桥粒柯林斯和钙粘蛋白的特异性靶向其邻近， 生物化学上不同的膜结构域将通过检查 这些分子嵌合体的连接定位。 这些研究 应该提供新的见解的具体作用的桥粒柯林斯， 细胞-细胞粘附以及水疱病的发病机制 寻常型天疱疮

The long term goal of this project is to characterize the role of desmocollins in cell-cell adhesion. Desmocollins are major glycoprotein components of the desmosome, and the targets of adhesion-disrupting antibodies present in the sera of patients with the severe blistering disease pemphigus vulgaris. Structurally, they form a distinct subset of the cadherins, a family of cell-cell adhesion and recognition molecules. Desmocollins occur as a number of tissue-specific isoforms generated by alternative splicing. The precise roles of these isoforms are not known. It is hypothesized that they are essential to the adhesive mechanism of the desmosome and may play a role in cellular recognition, cytoskeletal binding and the reception and transduction of initial cell-cell contact signals. The distribution of the desmocollin isoforms in both adult tissues and during embryonic development will be examined immunochemically and by PCR techniques to determine whether the pattern of expression is compatible with a role in morphogenesis. The interactions of the isoforms with other junctional components and with kinases will be examined, by co-precipitation and in vitro binding assays, to identify whether they function in signal transduction and/or cytoskeletal binding. Similar techniques will be used to define whether their association in the plane of the membrane is homotypic or heterotypic. The sequences that mediate and regulate the binding affinity of these molecules will be studied by comparing the capacity of wild type and recombinant desmocollins to support cell-cell adhesion and the ability of adhesion disrupting antibodies to interfere with this process. The sequences that govern the specific targeting of desmocollins and cadherins to their neighboring but biochemically distinct membrane domains will be studied by examining the junctional localization of chimeras of these molecules. These studies should provide new insights into the specific role of the desmocollins in cell-cell adhesion as well as the pathogenesis of the blistering disease pemphigus vulgaris.