Structure of astrotactin-2: a conserved vertebrate-specific and perforin-like membrane protein involved in neuronal development.
Structure of astrotactin-2: a conserved vertebrate-specific and perforin-like membrane protein involved in neuronal development.
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DOI：
10.1098/rsob.160053
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发表时间：
2016-05
期刊：
影响因子：
5.8
通讯作者：
Gilbert R
中科院分区：
文献类型：
--
作者：
Ni T;Harlos K;Gilbert R
脊椎动物特异性蛋白astrotactin-1和2（ASTN-1和ASTN-2）是已知在神经发育中起关键作用的膜穿孔素样蛋白，而ASTN-2已与毛细胞中的平面细胞极性通路相关。与它们相关的遗传变异与各种神经发育障碍和其他神经病理学有关，包括阿尔茨海默病的晚期发作。在这里，我们提出了大多数内体区域的ASTN-2的结构，显示它是由一个独特的组合的多肽折叠：穿孔素样结构域，最小的表皮生长因子样模块，纤连蛋白III型结构域和膜联蛋白样结构域的独特形式。穿孔素样结构域与膜攻击复合物穿孔素（MACPF）蛋白家族的其他成员不同，表明ASTN-2不形成孔。结构和生物物理数据表明，ASTN-2（而不是ASTN-1）结合肌醇三磷酸，这表明膜识别或二级信使调节其活性的机制。膜联蛋白样结构域是最接近的折叠重复三个人膜联蛋白V和类似的结合钙，但股份没有序列同源性与它。总体而言，我们的结构提供了第一个原子分辨率描述的MACPF蛋白参与发展，同时突出了独特的功能ASTN-2负责其活动。
The vertebrate-specific proteins astrotactin-1 and 2 (ASTN-1 and ASTN-2) are integral membrane perforin-like proteins known to play critical roles in neurodevelopment, while ASTN-2 has been linked to the planar cell polarity pathway in hair cells. Genetic variations associated with them are linked to a variety of neurodevelopmental disorders and other neurological pathologies, including an advanced onset of Alzheimer's disease. Here we present the structure of the majority endosomal region of ASTN-2, showing it to consist of a unique combination of polypeptide folds: a perforin-like domain, a minimal epidermal growth factor-like module, a unique form of fibronectin type III domain and an annexin-like domain. The perforin-like domain differs from that of other members of the membrane attack complex-perforin (MACPF) protein family in ways that suggest ASTN-2 does not form pores. Structural and biophysical data show that ASTN-2 (but not ASTN-1) binds inositol triphosphates, suggesting a mechanism for membrane recognition or secondary messenger regulation of its activity. The annexin-like domain is closest in fold to repeat three of human annexin V and similarly binds calcium, and yet shares no sequence homology with it. Overall, our structure provides the first atomic-resolution description of a MACPF protein involved in development, while highlighting distinctive features of ASTN-2 responsible for its activity.