An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient
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.
|Persistent URL||dx.doi.org/10.1038/s41589-018-0222-1, hdl.handle.net/1765/115210|
|Journal||Nature Chemical Biology|
Quancard, J., Klein, T, Fung, S.Y., Renatus, M., Hughes, N., Israel, L., … Overall, C.M. (2019). An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient. Nature Chemical Biology, 15(3), 304–30+. doi:10.1038/s41589-018-0222-1