An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient
2019
MALT1
paracaspaseis central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of
MALT1that 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
MALT1Trp580-to-serine mutation who suffered from
combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the
paracaspaseand C-terminal immunoglobulin
MALT1domains 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
MALT1protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout,
MALT1substrate cleavage was partly recovered. Thus, a molecular corrector rescues an
enzyme deficiencyby substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies.
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Correction
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