Interactions in the network of Usher syndrome type 1 proteins
Interactions in the network of Usher syndrome type 1 proteins
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DOI：
10.1093/hmg/ddi031
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Petit, C
中科院分区：
文献类型：
--
作者：
Adato, A;Michel, V;Petit, C
myosin VIIa, harmonin（一种PDZ结构域蛋白），cadherin 23， protocadherin 15和sans（一种推定的支架蛋白）的缺陷是五种类型的Usher综合征I型（USH1）的基础。所有这些蛋白的小鼠突变体表现出毛束的紊乱，毛束是内耳感觉细胞、耳蜗和前庭毛细胞的机械传导接受结构。我们之前已经证明了和谐蛋白与钙粘蛋白23和肌球蛋白via相互作用。在这里，我们解决了五个已知的USH1蛋白之间的相互作用的程度。我们建立了先前提出的sans-harmonin相互作用，并发现sans也与myosin via结合。我们发现sans可以形成同质结构，和声蛋白b可以与所有的和声蛋白异构体相互作用。我们发现和谐蛋白也与原钙粘蛋白15结合。这些相互作用的分子特征表明，通过与5个USH1蛋白中的4个结合，和声蛋白的第一个PDZ结构域（PDZ1）在该网络中起核心作用。我们定位于耳蜗顶区和前庭毛细胞体角质层下。与其他四种已知的USH1蛋白相比，在立体纤毛中没有检测到无标记。我们认为，通过与肌凝蛋白VIIa和/或和谐蛋白的结合，sans通过调节USH1蛋白通往立体纤毛的运输来控制毛束的凝聚力和正常发育。
Defects in myosin VIIa, harmonin (a PDZ domain protein), cadherin 23, protocadherin 15 and sans (a putative scaffolding protein), underlie five forms of Usher syndrome type I (USH1). Mouse mutants for all these proteins exhibit disorganization of their hair bundle, which is the mechanotransduction receptive structure of the inner ear sensory cells, the cochlear and vestibular hair cells. We have previously demonstrated that harmonin interacts with cadherin 23 and myosin VIIa. Here we address the extent of interactions between the five known USH1 proteins. We establish the previously suggested sans-harmonin interaction and find that sans also binds to myosin VIIa. We show that sans can form homomeric structures and that harmonin b can interact with all harmonin isoforms. We reveal that harmonin also binds to protocadherin 15. Molecular characterization of these interactions indicates that through its binding to four of the five USH1 proteins, the first PDZ domain (PDZ1) of harmonin plays a central role in this network. We localize sans in the apical region of cochlear and vestibular hair cell bodies underneath the cuticular plate. In contrast to the other four known USH1 proteins, no sans labeling was detected within the stereocilia. We propose that via its binding to myosin VIIa and/or harmonin, sans controls the hair bundle cohesion and proper development by regulating the traffic of USH1 proteins en route to the stereocilia.