Structural basis of the adaptive molecular recognition by MMP9
Structural basis of the adaptive molecular recognition by MMP9
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DOI：
10.1016/s0022-2836(02)00558-2
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发表时间：
2002-07-26
影响因子：
5.6
通讯作者：
Brandstetter, H
中科院分区：
文献类型：
--
作者：
Cha, HJ;Kopetzki, E;Brandstetter, H
基质金属蛋白酶（MMPs）对细胞外基质成分的降解至关重要，因此需要严格调节。几乎所有的MMPs都有一个同源的c端血红素样结构域（PEX）。除了在大分子底物加工中起作用外，PEX结构域似乎在调节MMP的激活、定位和抑制中起主要作用。MMP9的一个有趣的特性是它能够结合参与这些调节过程的不同蛋白质，并在其PEX结构域的重叠识别位点上具有高亲和力。通过PEX9二聚体的晶体结构，我们提出了PEX结构域如何完成这些不同角色的第一个例子。PEX9的叶片IV介导非共价和主要疏水二聚化接触。叶片III，特别是叶片IV的大位移伴随着二聚化，导致明显不对称的同型二聚体结构。这种不对称提供了一种新的适应性蛋白识别机制，其中不同的蛋白（PEX9、PEX1和TIMP1）可以在重叠位点以高亲和力结合PEX9。最后，该结构说明了二聚化如何在物理化学和功能水平上产生新的性质。(C) 2002 Elsevier Science Ltd.版权所有。
Matrix metalloproteinase (MMPs) are critical for the degradation of extracellular matrix components and, therefore, need to be regulated tightly. Almost all MMPs share a homologous C-terminal haemopexin-like domain (PEX). Besides its role in macromolecular substrate processing, the PEX domains appear to play a major role in regulating MMP activation, localisation and inhibition. One intriguing property of MMP9 is its competence to bind different proteins, involved in these regulatory processes, with high affinity at an overlapping recognition site on its PEX domain. With the crystal structure of the PEX9 dimer, we present the first example of how PEX domains accomplish these diverse roles. Blade IV of PEX9 mediates the non-covalent and predominantly hydrophobic dimerisation contact. Large shifts of blade III and, in particular, blade IV, accompany the dimerisation, resulting in a remarkably asymmetric homodimeric structure. The asymmetry provides a novel mechanism of adaptive protein recognition, where different proteins (PEX9, PEX1, and TIMP1) can bind with high affinity to PEX9 at an overlapping site. Finally, the structure illustrates how the dimerisation generates new properties on both a physico-chemical and functional level. (C) 2002 Elsevier Science Ltd. All rights reserved.