Crystal Structures of Matriptase in Complex with Its Inhibitor Hepatocyte Growth Factor Activator Inhibitor-1
Crystal Structures of Matriptase in Complex with Its Inhibitor Hepatocyte Growth Factor Activator Inhibitor-1
复制标题
Matriptase与其抑制剂肝细胞生长因子激活剂Inhibitor-1复合物的晶体结构
DOI：
10.1074/jbc.m113.454611
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发表时间：
2013-04-19
影响因子：
4.8
通讯作者：
Ngo, Jacky Chi Ki
中科院分区：
文献类型：
--
作者：
Zhao, Baoyu;Yuan, Cai;Ngo, Jacky Chi Ki
Mattritase是一种S1类胰酶家族的II型跨膜型丝氨酸蛋白酶，表达于几乎所有正常的人上皮细胞表面，并存在于生物液体状的人乳中。在某些上皮源性癌细胞中，Mattritase的过度表达与肿瘤的进展有关。Mattritase受其同源抑制物肝细胞生长因子激活物抑制物-1(HAI-1)的严格调控。已有研究表明，HAI-1对松茸酶的抑制作用与HAI-1的kunitz域I(Kd1)有关，而与knitz域II(Kd2)无关。为了研究HAI-1抑制Mattritase的分子基础，我们将Mattritase丝氨酸蛋白酶结构域的几种晶体结构与HAI-1的片段结合在一起。基于这些结构，我们发现Kd1的结合模式与先前预测的不同。与肝细胞生长因子激活剂、HAI-1 Kd1和Matritase、向日葵胰蛋白酶抑制物-1复合体不同，P3精氨酸残基占据了Mattritase的S3专一性口袋，而不是S4口袋。Mattritase的60个长环与HAI-1直接接触，但即使在复合体中也保持灵活，其顶端不与Kd1紧密结合。这一独特的60环与Kd1之间的相互作用可能为提高Kd1对Mattritase的特异性和抑制活性提供了机会。此外，Kd1与HAI-1Kd2的同源模型的比较合理地解释了为什么Kd1而不是Kd2对HAI-1抑制Mattritase活性负责的结构基础。
Matriptase, a type II trans-membrane serine protease of the S1 trypsin-like family, is expressed on the surface of nearly all normal human epithelium and found in biological fluid-like human milk. Matriptase overexpression has been implicated in tumor progression in certain epithelium-derived cancer cells. Matriptase is tightly regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). It has been demonstrated that the Kunitz domain I (KD1) but not Kunitz domain II (KD2) of HAI-1 is responsible for the inhibitory activity of HAI-1 against matriptase. To investigate the molecular basis of inhibition of matriptase by HAI-1, we solved several crystal structures of matriptase serine protease domain in complex with the fragments of HAI-1. Based on these structures, we found that the binding of KD1 was different from previously predicted binding mode. The P3 arginine residue occupies the S3 specificity pocket of matriptase, but not the S4 pocket as in the cases of hepatocyte growth factor activator.HAI-1 KD1 and matriptase.sunflower trypsin inhibitor-1 complexes. The long 60-loop of matriptase makes direct contact with HAI-1 but remains flexible even in the complexes, and its apex does not bind with KD1 tightly. The interactions between this unique 60-loop and KD1 may provide an opportunity to increase the specificity and inhibitory activity of KD1 for matriptase. Furthermore, comparison between KD1 and a homology model of HAI-1 KD2 rationalizes the structural basis of why KD1 but not KD2 is responsible for the inhibitory activity of HAI-1 against matriptase.