Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
Nat Chem Biol. 2019 Mar;15(3):304-313. doi: 10.1038/s41589-018-0222-1. Epub 2019 Jan 28.
MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies.
MALT1 连接酶的别构效应是中央对于淋巴细胞抗原依赖性反应，包括 NF-κB 的激活。我们发现了对 MALT1 具有纳米级选择性的别构抑制剂，它们通过取代色氨酸 580 的侧链结合，将蛋白酶锁定在非活性构象中。有趣的是，我们之前曾发现过一名 MALT1 色氨酸 580 到丝氨酸突变的纯合患者，患有联合免疫缺陷。我们表明，色氨酸的缺失削弱了连接酶和 C 末端免疫球蛋白 MALT1 结构域之间的相互作用，导致蛋白质不稳定、蛋白水平和功能降低。当结合别构抑制剂的效力增加时，我们发现 MALT1-W580S 的稳定性增加比例与野生型 MALT1 相当。通过恢复稳定的 MALT1 蛋白水平，最有效的别构抑制剂可恢复患者淋巴细胞中的 NF-κB 和 JNK 信号。在化合物洗脱后，MALT1 底物的切割部分恢复。因此，分子矫正剂通过取代突变残基来挽救酶缺陷，为其他缺陷中增加突变酶活性的新的潜在精准治疗方法提供了启示。
