A variable cytoplasmic domain segment is necessary for γ-protocadherin trafficking and tubulation in the endosome/lysosome pathway.
A variable cytoplasmic domain segment is necessary for γ-protocadherin trafficking and tubulation in the endosome/lysosome pathway.
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DOI：
10.1091/mbc.e11-04-0283
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发表时间：
2011-11
影响因子：
3.3
通讯作者：
Phillips GR
中科院分区：
文献类型：
--
作者：
O'Leary R;Reilly JE;Hanson HH;Kang S;Lou N;Phillips GR
γ-原钙粘蛋白（Pcdh-γ）胞质结构域（VCD）的可变部分控制Pcdh-γ在内溶酶体系统中的运输和细胞器的调节。活性VCD片段在Pcdh-γA和Pcdh-γB亚家族中是保守的。突变的原钙粘蛋白（Pcdhs）排列在具有可变和恒定外显子的基因簇（α、β和γ）中。可变外显子编码钙粘蛋白和跨膜结构域以及胞质中的90个残基。14个Pcdh-αs和22个Pcdh-γs剪接到恒定外显子上，对于Pcdh-γs，其编码相同胞质部分的约120个残基。Pcdh-γ参与细胞-细胞相互作用，但在体内主要是细胞内的，Pcdh-γ基因被破坏的小鼠表现出增加的神经元细胞死亡，表明非常规作用。在Pcdh-γ细胞内相互作用方面，大多数注意力集中在恒定结构域。我们发现，可变胞质结构域（VCD）所需的贩运和细胞器的滋养细胞内溶酶体系统。恒定胞质结构域的缺失保留了完整分子的晚期内体/溶酶体运输和细胞器微管，而VCD的缺失或切除或Pcdh-γA3胞质结构域被Pcdh-α1或N-钙粘蛋白的胞质结构域取代显著改变了运输。VCD内的截短或内部缺失定义了内溶酶体途径中运输和转运所需的26个氨基酸片段。该活性VCD片段含有在Pcdh-γA和Pcdh-γB亚家族中保守的残基。因此，Pcdh-γs的VCD介导对Pcdh-γ运输至关重要的相互作用。
The variable portion of the γ-protocadherin (Pcdh-γ) cytoplasmic domain (VCD) controls Pcdh-γ trafficking and organelle tubulation in the endolysosome system. Active VCD segments are conserved in Pcdh-γA and Pcdh-γB subfamilies. Clustered protocadherins (Pcdhs) are arranged in gene clusters (α, β, and γ) with variable and constant exons. Variable exons encode cadherin and transmembrane domains and ∼90 cytoplasmic residues. The 14 Pcdh-αs and 22 Pcdh-γs are spliced to constant exons, which, for Pcdh-γs, encode ∼120 residues of an identical cytoplasmic moiety. Pcdh-γs participate in cell–cell interactions but are prominently intracellular in vivo, and mice with disrupted Pcdh-γ genes exhibit increased neuronal cell death, suggesting nonconventional roles. Most attention in terms of Pcdh-γ intracellular interactions has focused on the constant domain. We show that the variable cytoplasmic domain (VCD) is required for trafficking and organelle tubulation in the endolysosome system. Deletion of the constant cytoplasmic domain preserved the late endosomal/lysosomal trafficking and organelle tubulation observed for the intact molecule, whereas deletion or excision of the VCD or replacement of the Pcdh-γA3 cytoplasmic domain with that from Pcdh-α1 or N-cadherin dramatically altered trafficking. Truncations or internal deletions within the VCD defined a 26–amino acid segment required for trafficking and tubulation in the endolysosomal pathway. This active VCD segment contains residues that are conserved in Pcdh-γA and Pcdh-γB subfamilies. Thus the VCDs of Pcdh-γs mediate interactions critical for Pcdh-γ trafficking.