Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains
Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains
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DOI：
10.1016/j.jmb.2007.07.047
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发表时间：
2007-11-02
影响因子：
5.6
通讯作者：
Abbott, W. Mark
中科院分区：
文献类型：
--
作者：
Gerhardt, Stefan;Hassall, Giles;Abbott, W. Mark
蛋白酶的ADAMTS（具有血小板反应蛋白I型基序的去整合素样和金属蛋白酶结构域）家族在包括关节炎、癌症、血栓性血小板减少性紫癜和Ehlers-Danlos型VIIC和Weill-Marchesani遗传综合征的病理状况中起作用。在这里，我们报告的第一个晶体结构的ADAMTS家族的成员，ADAMTS-1。ADAMTS-1最初作为炎症相关基因克隆，已被证明参与组织重塑、伤口愈合和血管生成。晶体结构包含催化和去整合素样结构域，均为无底物形式和与抑制剂马立马司他复合的形式。催化结构域的整体折叠类似于相关的锌金属蛋白酶，例如基质金属蛋白酶和亚当斯（去整合素和金属蛋白酶）。活性位点含有预期的残基组织以配位锌，但具有比ADAM 33大得多的S1'选择性口袋。该结构还意外地揭示了双钙结合位点。同样令人惊讶的是，先前命名的去整合素样结构域与其他金属蛋白酶如ADAM 10的去整合素结构域没有结构同源性，而是在结构上与其他金属蛋白酶的富含半胱氨酸的结构域非常相似。因此，这项研究表明，在ADAMTS酶的命名法中的D（去整合素样）很可能是一个误称。ADAMTS-1富含半胱氨酸的结构域堆叠在活性位点上，表明可能具有调节作用。(C)2007爱思唯尔有限公司保留所有权利。
The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type I motifs) family of proteases plays a role in pathological conditions including arthritis, cancer, thrombotic thrombocytopenic purpura and the Ehlers-Danlos type VIIC and Weill-Marchesani genetic syndromes. Here, we report the first crystal structures for a member of the ADAMTS family, ADAMTS-1. Originally cloned as an inflammation associated gene, ADAMTS-1 has been shown to be involved in tissue remodelling, wound healing and angiogenesis. The crystal structures contain catalytic and disintegrin-like domains, both in the inhibitor-free form and in complex with the inhibitor marimastat. The overall fold of the catalytic domain is similar to related zinc metalloproteinases such as matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinases). The active site contains the expected organisation of residues to coordinate zinc but has a much larger S1' selectivity pocket than ADAM33. The structure also unexpectedly reveals a double calcium-binding site. Also surprisingly, the previously named disintegrin-like domain showed no structural homology to the disintegrin domains of other metalloproteinases such as ADAM10 but is instead very similar in structure to the cysteine-rich domains of other metalloproteinases. Thus, this study suggests that the D (for disintegrin-like) in the nomenclature of ADAMTS enzymes is likely to be a misnomer. The ADAMTS-1 cysteine-rich domain stacks against the active site, suggesting a possible regulatory role. (C) 2007 Elsevier Ltd. All rights reserved.