Proteins from the signal transduction ATPases with numerous domains (STAND) family are known to play an important role in innate immunity. However, it remains less well understood how they function in transcriptional regulation. MalT is a bacterial STAND that controls the Escherichia coli maltose system. Inactive MalT is sequestered by different inhibitory proteins such as MalY. Here, we show that MalY interacts with one oligomerization interface of MalT to form a 2:2 complex. MalY represses MalT activity by blocking its oligomerization and strengthening ADP-mediated MalT autoinhibition. A loop region N-terminal to the nucleotide-binding domain (NBD) of MalT has a dual role in mediating MalT autoinhibition and activation. Structural comparison shows that ligand-binding induced oligomerization is required for stabilizing the C-terminal domains and conferring DNA-binding activity. Together, our study reveals the mechanism whereby a prokaryotic STAND is inhibited by a repressor protein and offers insights into signaling by STAND transcription activators.

已知来自具有多个结构域的信号转导 ATP 酶 (STAND) 家族的蛋白质在先天免疫中发挥重要作用。然而，人们对它们在转录调控中如何发挥作用仍知之甚少。MalT 是一种控制大肠杆菌麦芽糖系统的细菌 STAND。无活性的 MalT 被不同的抑制蛋白（例如 MalY）隔离。在这里，我们证明 MalY 与 MalT 的一个寡聚界面相互作用，形成 2:2 复合物。MalY 通过阻断 MalT 寡聚化和加强 ADP 介导的 MalT 自抑制来抑制 MalT 活性。MalT 核苷酸结合域 (NBD) N 端的环区域在介导 MalT 自抑制和激活方面具有双重作用。结构比较表明，配体结合诱导的寡聚化对于稳定 C 末端结构域和赋予 DNA 结合活性是必需的。总之，我们的研究揭示了原核 STAND 被阻遏蛋白抑制的机制，并提供了对 STAND 转录激活剂信号传导的见解。