The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association.
The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association.
复制标题
DOI：
10.1186/s12860-015-0074-4
复制
发表时间：
2015-11-25
期刊：
影响因子：
--
通讯作者：
Phillips GR
中科院分区：
文献类型：
--
作者：
Shonubi A;Roman C;Phillips GR
聚集型原钙粘附素(Pcdhs)是由位于三个基因簇中的单个外显子编码的一大类神经钙粘附素蛋白。每个外显子编码一个胞外、跨膜和近端的细胞质结构域。这些“可变区”可以拼接到在簇末端编码的恒定的细胞质部分。Pcdh胞外结构域介导亲和细胞与细胞的结合，但其胞内结构域导致细胞内滞留，并可能负向调节Pcdh细胞与细胞的结合。Pcdhs可以在神经元和其他细胞的细胞表面发现，但与经典的钙粘附素不同，它也显著地运输到内溶酶体系统。先前发现，Pcdh-γA3胞浆结构域(VCD)可变部分中的一个片段被证明是内溶酶体运输所必需的。这表明，相同的VCD片段可以介导来自不同簇的Pcdh之间的细胞质关联。Vcd区域内的内部缺失(这里称为Vcd基序)破坏了Pcdh-γA3在内溶体系统中的贩运，而Vcd基序外的缺失不影响贩运。结果表明，Pcdhs通过VCD内的一个基序进行细胞质联结，这对Pcdh的运输是至关重要的。鉴于VCD基序的截断改变了Pcdh的内溶体运输，这里描述的VCD相互作用可能为了解Pcdh介导的细胞-细胞相互作用的动态性质提供新的见解。
Clustered protocadherins (Pcdhs) are a large family of neural cadherin-like proteins encoded by individual exons located within three gene clusters. Each exon codes an extracellular, transmembrane, and proximal cytoplasmic domain. These “variable” regions may be spliced to a constant cytoplasmic moiety encoded at the end of a cluster. Pcdh extracellular domains mediate homophilic cell-cell binding but their cytoplasmic domains cause intracellular retention and may negatively regulate Pcdh cell-cell binding. Pcdhs can be found at the cell surface in neurons and other cells but are also, unlike classical cadherins, prominently trafficked to the endolysosome system. It was previously found that a segment within the variable portion of the Pcdh-γA3 cytoplasmic domain (VCD) was shown to be necessary for endolysosomal trafficking. Here it is shown that this same VCD segment can mediate cytoplasmic association among Pcdhs from the different clusters. Internal deletions within this VCD region (termed here the VCD motif) that disrupt the association altered trafficking of Pcdh-γA3 in the endolysosomal system while deletions outside VCD motif did not affect trafficking. The results show that Pcdhs associate cytoplasmically via a motif within the VCD and that this is critical for Pcdh trafficking. Given that truncation at the VCD motif alters endolysosomal trafficking of Pcdhs, the VCD interaction described here may provide new insights into the dynamic nature of Pcdh mediated cell-cell interactions.