ANKS4B Is Essential for Intermicrovillar Adhesion Complex Formation
ANKS4B Is Essential for Intermicrovillar Adhesion Complex Formation
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DOI：
10.1016/j.devcel.2015.12.022
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发表时间：
2016-01-25
影响因子：
11.8
通讯作者：
Tyska, Matthew J.
中科院分区：
文献类型：
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作者：
Crawley, Scott W.;Weck, Meredith L.;Tyska, Matthew J.
运输和感觉上皮细胞利用原钙粘蛋白为基础的粘附形成顶端特化。在肠细胞刷状边界，原钙粘蛋白的功能需要细胞质结合伙伴的复合体，尽管这种复合体的组成和控制其组装的逻辑仍然知之甚少。我们发现含有4B的锚蛋白重复和无菌基序结构域（ANKS4B）定位于粘附的刷状边缘微绒毛的尖端，对微绒毛间的粘附至关重要。ANKS4B与USH1C和MYO7B相互作用，后者将原钙粘蛋白连接到肌动蛋白细胞骨架。ANKS4B和USH1C也在MYO7B货物结合尾部的不同位点结合。然而，只有当ANKS4B和MYO7B首先被USH1C激活时，三方复合物才会形成。这项研究揭示了ANKS4B在刷状边界组装中的重要作用，揭示了驱动微绒毛间粘附的分子相互作用的层次结构，并使我们了解由USH1C和锚蛋白重复序列蛋白突变引起的疾病，如Usher综合征。
Transporting and sensory epithelial cells shape apical specializations using protocadherin-based adhesion. In the enterocyte brush border, protocadherin function requires a complex of cytoplasmic binding partners, although the composition of this complex and logic governing its assembly remain poorly understood. We found that ankyrin repeat and sterile a motif domain containing 4B (ANKS4B) localizes to the tips of adherent brush border microvilli and is essential for intermicrovillar adhesion. ANKS4B interacts with USH1C and MYO7B, which link protocadherins to the actin cytoskeleton. ANKS4B and USH1C also bind to the MYO7B cargo-binding tail at distinct sites. However, a tripartite complex only forms if ANKS4B and MYO7B are first activated by USH1C. This study uncovers an essential role for ANKS4B in brush border assembly, reveals a hierarchy in the molecular interactions that drive intermicrovillar adhesion, and informs our understanding of diseases caused by mutations in USH1C and ankyrin repeat proteins, such as Usher syndrome.