A single divergent exon inhibits ankyrin-B association with the plasma membrane.
A single divergent exon inhibits ankyrin-B association with the plasma membrane.
复制标题
DOI：
10.1074/jbc.m113.465328
复制
发表时间：
2013-05-24
期刊：
影响因子：
--
通讯作者：
Bennett V
中科院分区：
文献类型：
--
作者：
He M;Tseng WC;Bennett V
背景：锚定蛋白b在细胞内，而锚定蛋白g与质膜相关。结果：ANK重复结构域和ZU52-UPA模块之间的锚蛋白b特异性连接物抑制锚蛋白b与膜蛋白伴侣的结合以及上皮细胞和神经元的质膜定位。结论：连接区对锚蛋白的功能差异起一定作用。意义：本研究解释了锚蛋白在质膜定位中的独特行为。脊椎动物锚定蛋白b和锚定蛋白g在脊索动物进化之初具有高度的序列相似性和结构相似性以及来自同一祖先基因的共同起源，但它们却表现出不同的亚细胞定位和功能。以往对锚蛋白家族多样性的研究主要集中在c端调控域。在这里，我们发现了一种锚蛋白b特异性连接肽，将锚蛋白重复结构域连接到ZU52-UPA模块，抑制锚蛋白b与膜蛋白伴侣E-cadherin和神经束蛋白186的结合，并阻止锚蛋白b与上皮侧膜和神经元质膜的结合。自抑制所需的锚蛋白- b连接子残基由一个小外显子编码，该外显子在锚蛋白家族成员之间高度分化，但在锚蛋白- b谱系中保守。我们发现，锚蛋白b连接体通过分子内相互作用抑制ANK重复结构域的活性，可能与ANK重复螺线管表面的凹槽相互作用，从而调节锚蛋白b与其结合伙伴之间的亲和力。这些结果为锚蛋白b和锚蛋白g如何在质膜关联中获得显著差异同时保持整体高水平的序列相似性提供了一个简单的进化解释。
Background: Ankyrin-B is intracellular, whereas ankyrin-G associates with plasma membranes. Results: An ankyrin-B-specific linker between the ANK repeat domain and the ZU52-UPA module inhibits ankyrin-B binding to membrane protein partners and localization to plasma membranes of epithelial cells and neurons. Conclusion: The linker region contributes to functional differences between ankyrins. Significance: This work explains the distinct behavior of ankyrins regarding plasma membrane localization. Vertebrate ankyrin-B and ankyrin-G exhibit divergent subcellular localization and function despite their high sequence and structural similarity and common origin from a single ancestral gene at the onset of chordate evolution. Previous studies of ankyrin family diversity have focused on the C-terminal regulatory domain. Here, we identify an ankyrin-B-specific linker peptide connecting the ankyrin repeat domain to the ZU52-UPA module that inhibits binding of ankyrin-B to membrane protein partners E-cadherin and neurofascin 186 and prevents association of ankyrin-B with epithelial lateral membranes as well as neuronal plasma membranes. The residues of the ankyrin-B linker required for autoinhibition are encoded by a small exon that is highly divergent between ankyrin family members but conserved in the ankyrin-B lineage. We show that the ankyrin-B linker suppresses activity of the ANK repeat domain through an intramolecular interaction, likely with a groove on the surface of the ANK repeat solenoid, thereby regulating the affinities between ankyrin-B and its binding partners. These results provide a simple evolutionary explanation for how ankyrin-B and ankyrin-G have acquired striking differences in their plasma membrane association while maintaining overall high levels of sequence similarity.