An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: Relationship to cystatins and the tumor suppressor TIG1
An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: Relationship to cystatins and the tumor suppressor TIG1
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DOI：
10.1016/j.str.2004.12.013
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发表时间：
2005-02-01
期刊：
影响因子：
5.7
通讯作者：
Martin, JL
中科院分区：
文献类型：
--
作者：
Aagaard, A;Listwan, P;Martin, JL
Latexin是唯一已知的哺乳动物羧肽酶抑制剂，与植物和寄生虫抑制剂没有可检测的序列相似性，但它与人类推定的肿瘤抑制蛋白TIG1相关。Latexin在发育中的大脑中表达，我们发现它在炎症中起作用，因为它以高水平表达，并且与其他蛋白酶抑制剂和潜在的蛋白酶靶标一起在巨噬细胞中可诱导。在1.83埃分辨率下解析的小鼠latexin的晶体结构显示与其他羧肽酶抑制剂没有结构关系。此外，尽管缺乏可检测的序列重复，该结构包含两个拓扑相似的结构域相关的伪二重对称。令人惊讶的是，这些结构域共享半胱氨酸蛋白酶抑制剂折叠结构中发现的蛋白质，抑制半胱氨酸蛋白酶，这表明进化和可能的功能关系。肿瘤抑制蛋白TIG1的结构被建模，揭示了其假定的膜结合表面。
Latexin, the only known mammalian carboxypeptidase inhibitor, has no detectable sequence similarity with plant and parasite inhibitors, but it is related to a human putative tumor suppressor protein, TIG1. Latexin is expressed in the developing brain, and we find that it plays a role in inflammation, as it is expressed at high levels and is inducible in macrophages in concert with other protease inhibitors and potential protease targets. The crystal structure of mouse latexin, solved at 1.83 Angstrom resolution, shows no structural relationship with other carboxypeptidase inhibitors. Furthermore, despite a lack of detectable sequence duplication, the structure incorporates two topologically analogous domains related by pseudo two-fold symmetry. Surprisingly, these domains share a cystatin fold architecture found in proteins that inhibit cysteine proteases, suggesting an evolutionary and possibly functional relationship. The structure of the tumor suppressor protein TIG1 was modeled, revealing its putative membrane binding surface.