Whirlin complexes with p55 at the stereocilia tip during hair cell development
Whirlin complexes with p55 at the stereocilia tip during hair cell development
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DOI：
10.1073/pnas.0600923103
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发表时间：
2006-07-18
影响因子：
11.1
通讯作者：
Brown, Steve D. M.
中科院分区：
文献类型：
--
作者：
Mburu, Philomena;Kikkawa, Yoshiaki;Brown, Steve D. M.
哺乳动物的听力依赖于内耳毛细胞表面充满肌动蛋白的立体纤毛的适当发育。Whirlin是一种含有PDZ结构域的蛋白质，在立体纤毛顶端表达，通过Whirlin基因的突变，已知在立体纤毛发育中发挥关键作用。我们发现Whirlin与膜相关鸟苷酸激酶(MAGUK)蛋白--红细胞蛋白P55相互作用(P55)。P55在组成纤毛束的长毛纤毛细胞和周围较短的纤毛结构中表达。P55与红细胞中的4.1R蛋白相互作用，我们发现4.1R也在立体纤毛结构中表达，其模式与P55相同。Whirlin基因(Whirler)和肌球蛋白XVA基因(Shaker2)的突变会影响立体纤毛的发育，并导致立体纤毛的P55和4.1R标记的早期消融。相关的Maguk蛋白钙-钙调蛋白丝氨酸激酶(CASK)也在外毛细胞和内毛细胞的纤毛中表达，并局限于纤毛束。CASK与神经元组织中的4.1N蛋白相互作用，我们发现4.1N在立体纤毛中表达，其模式与CASK相同。与p55不同的是，桶标记在Whirler突变体中几乎没有减少标记，在摇晃突变体中不受影响。同样，4.1N在立体纤毛中的表达在Whirler和Shaker2突变体中没有改变。P55和蛋白4.1R形成对红细胞内肌动蛋白细胞骨架组装至关重要的复合体，而Whirlin与P55的相互作用表明它在毛细胞立体纤毛中发挥类似的作用。
Hearing in mammals depends upon the proper development of actin-filled stereocilia at the hair cell surface in the inner ear. Whirlin, a PDZ domain-containing protein, is expressed at stereocilia tips and, by virtue of mutations in the whirlin gene, is known to play a key role in stereocilia development. We show that whirlin interacts with the membrane-associated guanylate kinase (MAGUK) protein, erythrocyte protein p55 (p55). p55 is expressed in outer hair cells in long stereocilia that make up the stereocilia bundle as well as surrounding shorter stereocilia structures. p55 interacts with protein 4.1 R in erythrocytes, and we find that 4.1 R is also expressed in stereocilia structures with an identical pattern to p55. Mutations in the whirlin gene (whirler) and in the myosin XVa gene (shaker2) affect stereocilia development and lead to early ablation of p55 and 4.1R labeling of stereocilia. The related MAGUK protein Ca2+-calmodulin serine kinase (CASK) is also expressed in stereocilia in both outer and inner hair cells, where it is confined to the stereocilia bundle. CASK interacts with protein 4.1N in neuronal tissue, and we find that 4.1N is expressed in stereocilia with an identical pattern to CASK. Unlike p55, CASK labeling shows little diminution of labeling in the whirler mutant and is unaffected in the shaker2 mutant. Similarly, expression of 4.1N in stereocilia is unaltered in whirler and shaker2 mutants. p55 and protein 4.1R form complexes critical for actin cytoskeletal assembly in erythrocytes, and the interaction of whirlin with p55 indicates it plays a similar role in hair cell stereocilia.