The structural basis of cis and trans protocadherin interactions

拟议研究的总体目标是确定 成簇的原钙粘蛋白（Pcdhs）介导神经元的自我回避，这是所有神经元的一个关键特性。 神经系统Pcdhs编码在三个大的基因簇中，由替代基因控制， 启动子选择，在神经元中随机表达，使每个神经元血浆多样化 具有独特的Pcdh亚型的膜。这种多样性被认为是 作为单个神经元的分子“条形码”的基础， 自我和非自我之间的联系来调节自我回避。在上一个融资期，我们定义了 Pcdhs的功能结构，表明它们形成混杂的顺式二聚体识别单元 在它们的膜近端结构域，并识别其他Pcdh识别单位的反式 通过在域EC 1-EC 4中编码的大接口。我们用x射线绘制了这些界面 晶体学和诱变。Pcdhs编码足够的分集以 避免不适当地将非自我神经元识别为自我，这使得我们提出了两种替代方案， 模型，每个分子的细节，Pcdh功能。该提案旨在区分 这些模型来达到真正的机制Pcdh功能。

The overall objective of the proposed research is to determine the mechanism by which the clustered protocadherins (Pcdhs) mediate neuronal self-avoidance, a critical property of all nervous systems. The Pcdhs, encoded in three large gene clusters controlled by alternative promoter choice, are expressed stochastically in neurons, diversifying each neuronal plasma membranes with distinctive sets of Pcdh isoforms. This diversity is thought to underlie a molecular “barcode” for individual neurons, which allows cells to distinguish between self and non-self to mediate self-avoidance. In the prior funding period we defined the functional architecture of Pcdhs, showing that they form promiscuous cis-dimer recognition units in their membrane-proximal domains, and recognize other Pcdh recognition units in trans through large interfaces encoded in domains EC1-EC4. We mapped these interfaces by x-ray crystallography and mutagenesis. The requirement that Pcdhs encode sufficient diversity to avoid inappropriate recognition of non-self neurons as self, has led us to propose two alternative models, each in molecular detail, for Pcdh function. This proposal, is aimed at distinguishing these models to arrive at the true mechanism of Pcdh function.