Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family
Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family
复制标题
嗜热菌蛋白酶家族中锌金属蛋白酶自动加工的结构基础
DOI：
10.1073/pnas.1005681107
复制
发表时间：
2010-10-12
影响因子：
11.1
通讯作者：
Zhang, Yu-Zhong
中科院分区：
文献类型：
--
作者：
Gao, Xiang;Wang, Jue;Zhang, Yu-Zhong
嗜热菌蛋白酶样蛋白酶（TLPs）是一大类锌金属蛋白酶，其被合成为无活性的前体。具有长前肽（类似于200个残基）的TLP在通过难以捉摸的分子机制进行自动加工后经历成熟。我们报告的前两个晶体结构的一个典型的TLP，MCP-02的自动处理复合物。在自动处理的复合物中，Ala 205从先前共价连接的残基His 204向上移动33埃，表明His 204和Ala 205之间的肽键自动切割后，从酶原到自动处理的复合物发生了大的构象变化。催化结构域的八个N-末端残基（残基Ala 205-Gly 212）形成新的β-链，嵌套到另外两个β-链中。同时，与酶原相比，自动加工复合物的表观Tm增加20 ℃。前肽的逐步降解开始于Ser 49-Val 50和Gly 57-Leu 58处的两个连续切割，这导致前肽的分解和成熟MCP-02的形成。我们的研究结果为TLP成熟的分子机制提供了新的见解。
Thermolysin-like proteases (TLPs), a large group of zinc metalloproteases, are synthesized as inactive precursors. TLPs with a long propeptide (similar to 200 residues) undergo maturation following autoprocessing through an elusive molecular mechanism. We report the first two crystal structures for the autoprocessed complexes of a typical TLP, MCP-02. In the autoprocessed complex, Ala205 shifts upward by 33 angstrom from the previously covalently linked residue, His204, indicating that, following autocleavage of the peptide bond between His204 and Ala205, a large conformational change from the zymogen to the autoprocessed complex occurs. The eight N-terminal residues (residues Ala205-Gly212) of the catalytic domain form a new beta-strand, nestling into two other beta-strands. Simultaneously, the apparent T-m of the autoprocessed complex increases 20 degrees C compared to that of the zymogen. The stepwise degradation of the propeptide begins with two sequential cuttings at Ser49-Val50 and Gly57-Leu58, which lead to the disassembly of the propeptide and the formation of mature MCP-02. Our findings give new insights into the molecular mechanism of TLP maturation.