Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2.
Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2.
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DOI：
10.1093/hmg/ddi417
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发表时间：
2005-12
影响因子：
3.5
通讯作者：
J. Reiners;E. van Wijk;Tina Märker;U. Zimmermann;Karin Jürgens;H. te Brinke;N. Overlack;R. Roepman;M. Knipper;H. Kremer;U. Wolfrum
中科院分区：
文献类型：
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作者：
J. Reiners;E. van Wijk;Tina Märker;U. Zimmermann;Karin Jürgens;H. te Brinke;N. Overlack;R. Roepman;M. Knipper;H. Kremer;U. Wolfrum
亚瑟综合症（USH）是导致人类综合性聋盲的最常见原因。 USH 在临床和遗传上具有异质性，至少有 11 个染色体位点分配给三种 USH 类型（USH1A-G、USH2A-C、USH3A）。尽管不同的 USH 类型在人类中表现出几乎相同的表型，但已鉴定的 USH 基因编码的蛋白质属于非常不同的蛋白质类别和家族。我们和其他人最近报道了支架蛋白 Harmonin（USH1C 基因产物）将所有已识别的 USH1 分子整合到 USH1 蛋白网络中。在这里，我们研究了 USH2 分子和 USH1 蛋白质网络之间的关系。我们展示了支架蛋白 Harmonin (USH1C) 和 USH2A 蛋白 VLGR1 (USH2C) 以及 USH2B 候选蛋白 NBC3 之间的分子相互作用。我们将这些相互作用确定为 Harmonin 的 PDZ1 结构域与 USH2 蛋白和 NBC3 C 末端的 PDZ 结合基序之间的相互作用。我们证明 USH2A、VLGR1 和 NBC3 与 USH1 蛋白协调蛋白在视网膜感光器和内耳毛细胞的突触末端共表达。在毛细胞中，这些 USH 蛋白也定位于接收信号的静纤毛中。我们的数据表明，USH2 蛋白和 NBC3 是视网膜和内耳超分子 USH 蛋白网络的进一步伙伴，这为了解 USH2 蛋白和整个 USH 蛋白网络的功能提供了新的线索。这些发现为 USH1 和 USH2 病理生理学之间的分子联系提供了第一个证据。 USH 分子在与疾病相关的相互“相互作用组”中的组织可以解释 USH 的常见表型。
Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH.