Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2
Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2
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DOI：
10.1073/pnas.102185399
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
Tryggvason, K
中科院分区：
文献类型：
--
作者：
Morgunova, E;Tuuttila, A;Tryggvason, K
基质金属蛋白酶（MMP）是一个多域酶家族，参与结缔组织的生理降解以及肿瘤侵袭和关节炎等病理状态。除了转录调节外，MMP 还受到酶原激活和一类与催化位点结合的金属蛋白酶特异性组织抑制剂 (TIMP) 的控制。 TIMP-2 是一种有效的 MMP 抑制剂，但它也与潜在 MMP-2/明胶酶 A/IV 型胶原酶 (proMMP-2) 的独特细胞表面激活机制有关，一方面与 proMMP-2 的血红素结合蛋白结构域结合，另一方面与膜型 MMP 激活剂结合。人proMMP-2/TIMP-2复合物目前的晶体结构揭示了proMMP-2的血红素结合蛋白结构域和TIMP-2的C末端结构域之间的相互作用，使得MMP-2的催化位点和TIMP-2的抑制位点在空间上相距遥远。这两种蛋白质的界面接触的特征是由交替的疏水性和亲水性相互作用组成的两个不同的结合区域。这种独特的结构提供了如何实现非抑制性 MMP/TIMP 复合物形成的特异性的信息。
Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activation mechanism of latent MMP-2/gelatinase A/type IV collagenase (proMMP-2), through its binding to the hemopexin domain of proMMP-2 on the one hand and to a membrane-type MMP activator on the other. The present crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterized by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for noninhibitory MMP/TIMP complex formation is achieved.