The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.

中文翻译：

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MALT1通过其泛素结合Ig3结构域的变构活化。

适应性免疫反应和调节性T（Treg）细胞发育需要蛋白酶MALT1的催化活性，而失调的MALT1活性可能导致淋巴瘤。MALT1激活需要其在Ig3结构域内的赖氨酸644（K644）上进行单泛素化，该结构位于蛋白酶结构域附近。MALT1单泛素化的分子要求和单泛素化激活MALT1的机制仍然难以捉摸。在这里，我们显示Ig3结构域与泛素直接相互作用，并且完整的Ig3-泛素相互作用表面对于泛素与K644的缀合是必需的。此外，通过产生组成性活性MALT1突变体，克服了单泛素化的需求，我们揭示了泛素化位点K644，Ig3-蛋白酶相互作用表面之间的变构通讯，和蛋白酶结构域的活性位点。最后，我们表明，改变Ig3-泛素界面的MALT1突变体会影响T细胞的生物学反应。因此，Ig3结构域的泛素结合通过其生物学功能必不可少的变构机制促进MALT1激活。