Crystal structure of the catalytic domain of DESC1, a new member of the type II transmembrane serine proteinase family
Crystal structure of the catalytic domain of DESC1, a new member of the type II transmembrane serine proteinase family
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DOI：
10.1111/j.1742-4658.2007.05756.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.4
通讯作者：
Jacob, Uwe
中科院分区：
文献类型：
--
作者：
Kyrieleis, Otto J. P.;Huber, Robert;Jacob, Uwe
DESC 1是通过基因表达分析在头颈部鳞状细胞癌和正常组织中鉴定的。它属于II型跨膜多结构域丝氨酸蛋白酶（TTSP），一个扩展的丝氨酸蛋白酶家族，其成员在几种组织中差异表达。这些蛋白质的生物学作用目前正在调查中，虽然在某些情况下，它们参与特定的功能已被报道。这是肠肽酶、肝蛋白酶、间质蛋白酶和corin的情况。一些成员，包括DESC 1，与细胞分化相关，并已被描述为肿瘤标志物。TTSP属于II型跨膜蛋白，除了C-末端胰蛋白酶样丝氨酸蛋白酶结构域之外，其还显示不同的一组茎结构域、跨膜区段和短的N-末端胞质区域。基于序列分析，TTSP家族被细分为四个亚家族：hepsin/跨膜蛋白酶，丝氨酸（TMPRSS）; matriptase; corin;和人气道胰蛋白酶（HAT）/HAT样/DESC亚家族。hepsin和matriptase亚家族的成员在结构上是已知的，在这里，我们将DESC 1的晶体结构呈现为与苯甲脒复合的HAT/HAT样/DESC亚家族的第一个成员。DESC 1的蛋白酶结构域表现出胰蛋白酶样丝氨酸蛋白酶折叠，具有凝血酶样S1口袋、尿激酶型纤溶酶原激活剂型S2口袋以接受小残基，以及开放的疏水S3/S4腔以接受大的疏水残基。DESC 1的推导底物特异性明显不同于其他结构已知的TTSP。基于表面分析，我们提出了一个刚性域协会的N-末端SEA结构域的蛋白酶结构域的背面网站。
DESC1 was identified using gene-expression analysis between squamous cell carcinoma of the head and neck and normal tissue. It belongs to the type II transmembrane multidomain serine proteinases (TTSPs), an expanding family of serine proteinases, whose members are differentially expressed in several tissues. The biological role of these proteins is currently under investigation, although in some cases their participation in specific functions has been reported. This is the case for enteropeptidase, hepsin, matriptase and corin. Some members, including DESC1, are associated with cell differentiation and have been described as tumor markers. TTSPs belong to the type II transmembrane proteins that display, in addition to a C-terminal trypsin-like serine proteinase domain, a differing set of stem domains, a transmembrane segment and a short N-terminal cytoplasmic region. Based on sequence analysis, the TTSP family is subdivided into four subfamilies: hepsin/transmembrane proteinase, serine (TMPRSS); matriptase; corin; and the human airway trypsin (HAT)/HAT-like/DESC subfamily. Members of the hepsin and matriptase subfamilies are known structurally and here we present the crystal structure of DESC1 as a first member of the HAT/HAT-like/DESC subfamily in complex with benzamidine. The proteinase domain of DESC1 exhibits a trypsin-like serine proteinase fold with a thrombin-like S1 pocket, a urokinase-type plasminogen activator-type S2 pocket, to accept small residues, and an open hydrophobic S3/S4 cavity to accept large hydrophobic residues. The deduced substrate specificity for DESC1 differs markedly from that of other structurally known TTSPs. Based on surface analysis, we propose a rigid domain association for the N-terminal SEA domain with the back site of the proteinase domain.