A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.
A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.
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DOI：
10.1038/emboj.2010.18
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发表时间：
2010-04-07
期刊：
影响因子：
11.4
通讯作者：
Delmas, Patrick
中科院分区：
文献类型：
--
作者：
Giamarchi, Aurelie;Feng, Shuang;Rodat-Despoix, Lise;Xu, Yaoxian;Bubenshchikova, Ekaterina;Newby, Linda J.;Hao, Jizhe;Gaudioso, Christelle;Crest, Marcel;Lupas, Andrei N.;Honore, Eric;Williamson, Michael P.;Obara, Tomoko;Ong, Albert C. M.;Delmas, Patrick
常染色体显性多囊肾病（ADPKD）是由编码多囊蛋白-1 （PC1）和多囊蛋白-2 （PC2）的两个基因PKD1和PKD2突变引起的。早期的研究表明PC1和PC2组装成一个多囊蛋白复合物，与肾脏形态发生有关。PC2也会组装成功能不确定的同质体。然而，对于指导多囊蛋白复合物组装及其功能的分子机制知之甚少。我们已经在PC2的c端发现了一个卷曲的线圈，它作为PC1结合所必需的同二聚化结构域，但不是PC1的自寡聚化。二聚化缺陷的PC2突变体无法在质膜（PM）或PM-内质网（ER）连接处重建PC1/PC2复合物，但仍然可以作为ER Ca2+释放通道发挥作用。二聚化缺陷PC2突变体在斑马鱼中的表达导致囊性表型，但对器官侧性的影响较小。我们得出结论，PC2的c端二聚化指定了多囊蛋白复合物的形成，而不是er定位的PC2通道的形成。影响PC2 c端同源和异聚化的突变可能是ADPKD中囊肿形成的分子基础。
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self-oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca2+-release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C-terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo- and heteromerization are the likely molecular basis of cyst formation in ADPKD.
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DOI：
10.1016/j.str.2005.10.010
发表时间：
2006-03
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
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影响因子：
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作者：
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作者：
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影响因子：
4
作者：
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通讯作者：
Somlo, S
影响因子：
13.6
作者：
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通讯作者：
Sandford, R