Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, United States.
J Mol Biol. 2022 Mar 15;434(5):167413. doi: 10.1016/j.jmb.2021.167413. Epub 2021 Dec 20.
Alpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is triggered to entrap the protease. The structural basis behind the cleavage-induced transformation and the protease entrapment remains unclear. Here, we report cryo-EM structures of native- and intermediate-forms of the Xenopus laevis egg A2M homolog (A2Moo or ovomacroglobulin) tetramer at 3.7-4.1 Å and 6.4 Å resolution, respectively. In the native A2Moo tetramer, two pairs of dimers arrange into a cross-like configuration with four 60 Å-wide bait-exposing grooves. Each bait in the native form threads into an aperture formed by three macroglobulin domains (MG2, MG3, MG6). The bait is released from the narrowed aperture in the induced protomer of the intermediate form. We propose that the intact bait region works as a "latch-lock" to block futile A2M transformation until its protease-mediated cleavage.
α-2-巨球蛋白（A2M）是先天免疫系统中关键的泛蛋白酶抑制剂。当蛋白酶切割 A2M 的诱饵区域时，A2M 四聚体的全局结构发生转变，从而捕获蛋白酶。切割诱导的转变和蛋白酶捕获的结构基础仍不清楚。在这里，我们报道了非洲爪蟾卵 A2M 同源物（A2Moo 或卵巨球蛋白）四聚体的天然和中间形式的 cryo-EM 结构，分辨率分别为 3.7-4.1Å 和 6.4Å。在天然 A2Moo 四聚体中，两对二聚体排列成十字形结构，有四个 60Å 宽的诱饵暴露沟。天然形式的每个诱饵都穿过由三个巨球蛋白结构域（MG2、MG3、MG6）形成的孔。在中间形式的诱导原体中，诱饵从变窄的孔中释放出来。我们提出完整的诱饵区域充当“闩锁”，阻止无效的 A2M 转变，直到其被蛋白酶介导的切割。
