The solution structure of the MANEC-type domain from hepatocyte growth factor activator inhibitor-1 reveals an unexpected PAN/apple domain-type fold
The solution structure of the MANEC-type domain from hepatocyte growth factor activator inhibitor-1 reveals an unexpected PAN/apple domain-type fold
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DOI：
10.1042/bj20141236
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发表时间：
2015-03-01
影响因子：
4.1
通讯作者：
Jensen, Jan K.
中科院分区：
文献类型：
--
作者：
Hong, Zebin;Nowakowski, Michal;Jensen, Jan K.
十年前，N端八个半胱氨酸基序（MANEC）被定义为一个新的蛋白质结构域家族。该结构域仅存在于超过 400 个来自动物的多结构域 1 型跨膜蛋白的 N 末端。尽管含有大量 MANEC 的蛋白质，但只有一种在蛋白质水平上得到了表征：肝细胞生长因子激活剂抑制剂-1 (HAI-1)。 HAI-1 是一种必需蛋白质，因为基因敲除小鼠会因胎盘缺陷而在子宫内死亡。 HAI-1 是一种 matriptase、hepsin 和肝细胞生长因子 (HGF) 激活剂的抑制剂，这些丝氨酸蛋白酶在上皮发育、细胞生长和体内平衡中具有重要作用。这些蛋白酶的失调与皮肤病和癌症等病理状况有关。由于缺乏 MANEC 的结构信息，对 HAI-1 和其他含有 MANEC 的蛋白质的详细功能了解受到阻碍。尽管存在许多 MANEC 序列，但基于序列的数据库搜索无法预测结构同源性。在本文中，我们提出了 HAI-1 中 MANEC 结构域的 NMR 溶液结构，这是 MANEC 结构域家族中的第一个三维 (3D) 结构。出乎意料的是，MANEC 是 PAN/apple 结构域家族的一个新子类，具有自己的统一特征，例如两个额外的二硫键、两个扩展环区域和额外的 a 螺旋元件。正如其他含有 PAN/apple 结构域的蛋白质所示，我们提出 MANEC 结构域在分子内和分子间相互作用中具有类似的积极作用。该结构为进一步阐明HAI-1功能提供了工具，也为其他含MANEC蛋白的研究提供了参考。
Adecade ago, motif at N-terminus with eight-cysteines(MANEC) was defined as a new protein domain family. This domain is found exclusively at the N-terminus of >400 multi-domain type-1 transmembrane proteins from animals. Despite the large number of MANEC-containing proteins, only one has been characterized at the protein level: hepatocyte growth factor activator inhibitor-1 (HAI-1). HAI-1 is an essential protein, as knockout mice die in utero due to placental defects. HAI-1 is an inhibitor of matriptase, hepsin and hepatocyte growth factor (HGF) activator, all serine proteases with important roles in epithelial development, cell growth and homoeostasis. Dysregulation of these proteases has been causatively implicated in pathological conditions such as skin diseases and cancer. Detailed functional understanding of HAI-1 and other MANEC-containing proteins is hampered by the lack of structural information on MANEC. Although many MANEC sequences exist, sequence-based database searches fail to predict structural homology. In the present paper, we present the NMR solution structure of the MANEC domain from HAI-1, the first three-dimensional (3D) structure from the MANEC domain family. Unexpectedly, MANEC is a new subclass of the PAN/apple domain family, with its own unifying features, such as two additional disulfide bonds, two extended loop regions and additional a-helical elements. As shown for other PAN/apple domain-containing proteins, we propose a similar active role of the MANEC domain in intramolecular and intermolecular interactions. The structure provides a tool for the further elucidation of HAI-1 function as well as a reference for the study of other MANEC-containing proteins.